Bioinformatics-guided analysis uncovers TIGIT as an epigenetically regulated immunomodulator affecting immunotherapeutic sensitivity of gastric cancer

BACKGROUND: Immunomodulatory genes play significant roles in the regulation of immunological properties of gastric cancer, but the effect of epigenetic regulation of these genes on the immune properties is unknown. METHOD: I analyzed the methylation-expression correlation among all immunomodulators and compared with the non-immunomodulators. The association between epigenetically regulated immunomodulators (ERI) and tumor microenvironment is evaluated. A key immunomodulator TIGIT is further selected to investigate the potential value in the regulation of immunologic properties. Furthermore, the prognostic value and the immunotherapeutic potential of TIGIT are also explored. RESULT: Four genes are identified as ERIs based on the negative correlation between expression and methylation. Association analysis shows that three ERIs participate in the regulation of the immune microenvironment of gastric cancer. Among these ERIs, TIGIT is identified as a key immunomodulator. TIGIT is found to be significantly associated with immune properties. The high TIGIT expression group tends to display an active immune landscape. TIGIT expression is also found to be associated with survival and immunotherapeutic sensitivity. High TIGIT expression group has a favorable prognosis and is more likely to respond to immunotherapy than the low expression group. CONCLUSION: TIGIT is an epigenetically regulated immunomodulator of gastric cancer which can modify the immune activity and affect immunotherapeutic sensitivity. These findings can promote the research of epigenetic therapies and improve the survival of cancer patients by sensitizing tumors to immune therapies.

Structural, genetic, and serological elucidation of Streptococcus pneumoniae serogroup 24 serotypes: Discovery of a new serotype, 24C, with a variable capsule structure

Pneumococcal capsules are important in pneumococcal pathogenesis and vaccine development. Though conjugate vaccines have brought about a significant reduction in invasive pneumococcal disease (IPD) caused by vaccine serotypes, the relative serotype prevalence has shifted with dramatic emergence of serotype 24F in some countries. Herein, we describe fourteen isolates (thirteen IPD and one non-IPD) expressing a new capsule type, 24C, which resembles 24F but has a novel serological profile. We also describe the antigenic, biochemical, and genetic bases of 24F and 24C and the related serotypes 24A and 24B. Structural studies show that 24B, 24C, and 24F have identical polysaccharide backbones [β-Rib f- (1→4)-α-Rha p -(1→3)-β-Glc p NAc-(1→4)-β-Rha p -(1→4)-β-Glc p ] but with different side chains: 24F has arabinitol-phosphate, and 24B has ribitol-phosphate. 24C has a mixture of 24F and 24B repeating units, with ratio of ribitol to arabinitol being strain-dependent. In contrast, 24A capsule has a backbone without β-Rib f but with arabinitol-phosphate and phosphocholine side chains. These structures indicate that factor-sera 24d and 24e respectively recognize arabinitol and ribitol, which explains the serology of serogroup 24, including those of 24C. The structures can be genetically described by the bi-specificity of wcxG , capable of transferring arabinitol or ribitol when arabinitol is limiting. Arabinitol is likely not produced in 24B but is produced in reduced amounts in 24C due to various mutations in abpA or abpB genes. Our findings demonstrate how pneumococci modulate their capsule structure and immunologic properties with small genetic changes, thereby evading host immune responses. Our findings also suggest a potential for new capsule types within serogroup 24.

Impact of Excipients on Stability of Polymer Microparticles for Autoimmune Therapy

Therapies for autoimmune diseases such as multiple sclerosis and diabetes are not curative and cause significant challenges for patients. These include frequent, continued treatments required throughout the lifetime of the patient, as well as increased vulnerability to infection due to the non-specific action of therapies. Biomaterials have enabled progress in antigen-specific immunotherapies as carriers and delivery vehicles for immunomodulatory cargo. However, most of this work is in the preclinical stage, where small dosing requirements allow for on-demand preparation of immunotherapies. For clinical translation of these potential immunotherapies, manufacturing, preservation, storage, and stability are critical parameters that require greater attention. Here, we tested the stabilizing effects of excipients on the lyophilization of polymeric microparticles (MPs) designed for autoimmune therapy; these MPs are loaded with peptide self-antigen and a small molecule immunomodulator. We synthesized and lyophilized particles with three clinically relevant excipients: mannitol, trehalose, and sucrose. The biophysical properties of the formulations were assessed as a function of excipient formulation and stage of addition, then formulations were evaluated in primary immune cell culture. From a manufacturing perspective, excipients improved caking of lyophilized product, enabled more complete resuspension, increased product recovery, and led to smaller changes in MP size and size distribution over time. Cocultures of antigen-presenting cells and self-reactive T cells revealed that MPs lyophilized with excipients maintained tolerance-inducing function, even after significant storage times without refrigeration. These data demonstrate that excipients can be selected to drive favorable manufacturing properties without impacting the immunologic properties of the tolerogenic MPs.

Repair of Iliac Crest Defects with a Hydroxyapatite/Collagen Composite

Study Design: Retrospective study.Purpose: This study aimed to assess the effect of refilling with hydroxyapatite/collagen (HAp/Col) composite on an iliac crest defect after spinal fusion.Overview of Literature: The use of iliac crest bone graft has been the gold standard in spinal fusion for a long time because of its biological and non-immunologic properties. Few reports have addressed how bone defects recover after iliac crest bone harvest following spinal fusion.Methods: Cancellous bone was collected from the anterior iliac crest during lateral interbody fusion (LIF), and the bone void of the ilium was refilled with a porous HAp/Col composite. We assessed bone recovery using computed tomography (CT). From the 74 patients who underwent LIF between January 2015 and December 2016, we included 49 patients whose iliac crest could be evaluated using CT at 3 months and 1 year after the surgery.Results: Bone defects decreased in a time-dependent manner after the surgery. Cortical closure was observed in 28.5% of the cases 3 months after the surgery; at 1 year postoperatively, 95.9% of the patients had cortical closure. Complete repair of the cancellous bone was achieved in 57.1% of the patients at 3 months after the surgery and in 95.9% at 1 year after the surgery. There were no significant hematomas, infections, iliac crest fractures, or soft tissue herniation.Conclusions: Radiographic recovery of cortical and cancellous bone defects was achieved with high probability via refilling with HAp/Col composite over the 1-year period.

Immunologic Defense Mechanism in Human Milk

Breast feeding has been intensively campained throughout the country in the last decade, which is thought to be responsible for the decline of the incidence of gastroenteritis. One of the most important advantages of breast feeding is the immunologic properties of breast milk. The importance of breast milk in the protection of many infections of the newly born infants, who are naturally immunologically deficient, is well-established. Breast milk contains humoral as well as cellular immunity components, each component has its elements although it is possible to describe the role of each components, it is generally thought that the protective properties of human milk against infections in neonates and young babies are the results of interactions of many factors rather than the effect of solely each factor. The role of humoral (immunoglobulins) and cellular (macrophages, lymphocytes, and other cellular elements) immunity of human milk, especially its protective properties, is discussed in this article.