Chromatin regulation and immune escape

Antigens expressed by cancer cells target them for elimination by tumor-infiltrating T cells (1). But, despite T cell recognition, advanced malignancies are often fatally progressive. T cell inhibitory (checkpoint) receptors, including programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte–associated protein 4 (CTLA-4), contribute to immune suppression and dysfunction in tumors. Checkpoint inhibitors (CPIs) developed to block these pathways and derepress T cell activity have considerably improved outcomes for various cancer types. However, beyond certain rare and highly sensitive tumors (2), responses remain limited to a fraction of patients, and both primary and acquired resistance are frequently observed. Although much work has focused on defining and overcoming T cell–intrinsic inhibitory mechanisms, such as checkpoint expression, less is known about what regulates tumor cell sensitivity to T cell attack. On pages 801 and 770 of this issue, Miao et al. (3) and Pan et al. (4), respectively, find that chromatin remodeling pathways contribute to cancer cell immune resistance through control of interferon-stimulated gene (ISG) expression. This has implications for our understanding of why CPIs fail and suggests that targeting these pathways may enhance tumor immunotherapy

Cancer cell-intrinsic mechanisms driving acquired immune tolerance

Immune evasion is a hallmark of cancer, enabling tumors to survive contact with the host immune system and evade the cycle of immune recognition and destruction. Here, we review the current understanding of the cancer cell-intrinsic factors driving immune evasion. We focus on T cells as key effectors of anti-cancer immunity and argue that cancer cells evade immune destruction by gaining control over pathways that usually serve to maintain physiological tolerance to self. Using this framework, we place recent mechanistic advances in the understanding of cancer immune evasion into broad categories of control over T cell localization, antigen recognition, and acquisition of optimal effector function. We discuss the redundancy in the pathways involved and identify knowledge gaps that must be overcome to better target immune evasion, including the need for better, routinely available tools that incorporate the growing understanding of evasion mechanisms to stratify patients for therapy and trials

Controleld Morphology and Mechanical Characterisation of Electrospun Cellulose Acetate Fibre Webs

The purpose was to interpret the varying morphology of electrospun cellulose acetate (CA) fibres produced from single and binary solvent systems based on solubility parameters to identify processing conditions for the production of defect-free CA fibrous webs by electrospinning. The Hildebrand solubility parameter () and the radius of the sphere in the Hansen space () of acetone, acetic acid, water, N,N-dimethylacetamide (DMAc), methanol, and chloroform were examined and discussed for the electrospinning of CA. The Hildebrand solubility parameter () of acetone and DMAc were found to be within an appropriate range for the dissolution of CA. The suitability of the binary solvent system of acetone: DMAc (2 : 1) for the continuous electrospinning of defect-free CA fibres was confirmed. Electrospun webs exhibited improved tensile strength and modulus after heat and alkali treatment (deacetylation) of the as-spun material, and no major fibre morphological degradation occurred during the deacetylation process

Prevalence of Human T-Lymphotropic Virus Types I and II in Patients With Hematological Disorders in Isfahan, Iran

Background: Human T-cell lymphotropic virus types I and II (HTLV-I and HTLV-II) are deltaretroviruses which may cause leukemia, lymphoma and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In addition, HTLV-1 may be related to thalassemia and hemophilia cases after blood transfusion. Objectives: The aim of this study was evaluation of the prevalence of HTLVs in patients with hematological disorders (leukemia, thalassemia, lymphoma and hemophilia). Patients and Methods: This cross-sectional study was conducted during April to October 2012. A total of 101 serum samples were collected from patients and were stored at -20 degrees C. DNA was extracted from serum by an extraction kit. The extracted DNA was tested by polymerase chain reaction (PCR) for detection of HTLV-I and HTLV-II pol and tax gene sequences, respectively. Samples were collected from 67 (66.33%), 20 (19.80%), 4 (3.96%), and 10 (9.90%) patients with thalassemia, leukemia, lymphoma and hemophilia, respectively. Results: One thalassemia sample was HTLV-I positive, but none of the samples contained the genome of HTLV-II. The prevalence of HTLV-I in this study in patients with hematological disorders was 0.99%. Conclusions: The prevalence of HTLV-I in hematological disorders was similar to that of other parts of Iran. The present study revealed that HTLV-I screening should be performed before blood transfusion to reduce the risk of virus transmission in patients with hematological disorders. More study should be performed to detect these viruses in blood donors

Electrohydrodynamic atomization assisted encapsulation of bioactive compounds

Electrohydrodynamics atomization (Electrospraying) is a versatile technique to produce microspheres or beads from various materials by means of electrical forces. Electrospraying has numerous advantages over traditional methods in encapsulation: there is high encapsulation efficiency without unfavorable denaturation of bioactive molecules and an enhanced control over the size distribution of particles. This technique could be used for encapsulating bioactive molecules such as proteins, enzymes, vitamins, polyphenols, drugs and sensitive ingredients, for lots of purposes such as masking the bitter test of compounds, sustained releasing, the stability of compounds during process or shelf life of foods, etc. Living cells and spores could be encapsulated by this method for bioenvironmental purposes. Beads can be made by a wide range of food grade and natural biodegradable polymers including alginate, starch, carrageenan, chitosan zein, etc., which makes their use suitable in the development of new foods with enhanced properties and characteristics. Encapsulation by this method also achieves the ability of sustained and controlled release of bioactive compounds by foods, and increasing the effectiveness of such compounds along the time

Hypertension trials update

Hypertension is one of the most prevalent cardiovascular diseases and its treatment requires multimodal therapeutic approaches. This review aims to provide a summary and update on relevant evidence in hypertension research published in 2019/2020. These include trials dealing with the prognostic effect of systolic and diastolic blood pressure values, the association between hypertension and valve disease, reproducibility of masked and white-coat hypertension, and the prognostic importance of ambulatory and night-time blood pressure measurements. Treatment of hypertension focusing on elderly patients but also the potential cancer risk of thiazide diuretics, the valsartan recall, chronotherapy, and device-based hypertension therapy are discussed

How to design a MAMS-ROCI (aka DURATIONS) randomised trial: the REFINE-Lung case study

Background. The DURATIONS design has been recently proposed as a practical alternative to a standard two-arm non-inferiority design when the goal is to optimise some continuous aspect of treatment administration, e.g. duration or frequency, preserving efficacy but improving on secondary outcomes such as safety, costs or convenience. The main features of this design are that (i) it randomises patients to a moderate number of arms across the continuum and (ii) it uses a model to share information across arms. While papers published to date about the design have focused on analysis aspects, here we show how to design such a trial in practice. We use the REFINE-Lung trial as an example; this is a trial seeking the optimal frequency of immunotherapy treatment for non-small cell lung cancer patients. Because the aspect of treatment administration to optimise is frequency, rather than duration, we propose to rename the design as Multi-Arm Multi-Stage Response Over Continuous Intervention (MAMS-ROCI). Methods. We show how simulations can be used to design such a trial. We propose to use the ADEMP framework to plan such simulations, clearly specifying aims, data generating mechanisms, estimands, methods and performance measures before coding and analysing the simulations. We discuss the possible choices to be made using the REFINE-Lung trial as an example. Results. We describe all the choices made while designing the REFINE-Lung trial, and the results of the simulations performed. We justify our choice of total sample size based on these results. Conclusions. MAMS-ROCI trials can be designed using simulation studies that have to be carefully planned and conducted. REFINE-Lung has been designed using such an approach and we have shown how researchers could similarly design their own MAMS-ROCI trial.Comment: 25 pages, 1 table, 5 figure

What is the optimal duration, dose and frequency for anti-PD1 therapy of non-small cell lung cancer?

Over the past decade, immune checkpoint inhibitors (ICIs) have transformed the management of multiple malignancies including lung cancer. However, the optimal use of these agents in terms of duration, dose and administration frequency remains unknown. Focusing on anti-PD1 agents nivolumab and pembrolizumab in the context of non-small cell lung cancer, we argue that several lines of evidence suggest current administration regimens of these drugs may result in overtreatment with potentially important implications for cost, quality of life and toxicity. This review summarizes evidence for the scope to optimize anti-PD1 regimens, the limitations of existing data and potential approaches to solve these problems including with a novel multi-arm clinical trial design implemented in the recently opened REFINE-Lung study

Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells.

Tumours have developed strategies to interfere with most steps required for anti-tumour immune responses. Although many populations contribute to anti-tumour responses, tumour-infiltrating cytotoxic T cells dominate, hence, many suppressive strategies act to inhibit these. Tumour-associated T cells are frequently restricted to stromal zones rather than tumour islands, raising the possibility that the tumour microenvironment, where crosstalk between malignant and "normal" stromal cells exists, may be critical for T cell suppression. We provide evidence of direct interactions between stroma and T cells driving suppression, showing that cancer-associated fibroblasts (CAFs) sample, process and cross-present antigen, killing CD8+ T cells in an antigen-specific, antigen-dependent manner via PD-L2 and FASL. Inhibitory ligand expression is observed in CAFs from human tumours, and neutralisation of PD-L2 or FASL reactivates T cell cytotoxic capacity in vitro and in vivo. Thus, CAFs support T cell suppression within the tumour microenvironment by a mechanism dependent on immune checkpoint activation

Determination of developmental stages of embryo in the sea urchin, Echinometra mathaei

Sea Urchin is one of the most useful tools in developmental biology studies because this organism has the simplest kind of developmental stages. We aimed to determine developmental stages and timetable of Echinometra mathaei embryo (the species of Persian Gulf). The spawning of E. mathaei was induced by 0.5M KCl injection (1ml) into the coelomic cavity. After fertilization, embryos were placed in beakers and were incubated at 29°C and a salinity of 39 ppt until embryos reached the pluteus stage. The developmental stages of embryos and the timing of each stage including cleavage, morulae, blastula, gastrula, prism and pluteus larvae were studied under the microscope. Our results showed that after 30 hours from fertilization time, the embryos developed to pluteus larvae. E. mathaei had the shorter development time in comparison to the other Sea Urchin species. Therefore, it may be appropriate as a model organism in biological researches