Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system that can cause loss of motor function and is thought to result, in part, from chronic inflammation due to an antigen-specific T cell immune response. Current treatments suppress the immune system without antigen specificity, increasing the risks of cancer, chronic infection, and other long-term side effects. In this study, we show treatment of experimental autoimmune encephalomyelitis (EAE), a model of MS, by coencapsulating the immunodominant peptide of myelin oligodendrocyte glycoprotein (MOG) with dexamethasone (DXM) into acetalated dextran (Ac-DEX) microparticles (DXM/MOG/MPs) and administering the microparticles subcutaneously. The clinical score of the mice was reduced from 3.4 to 1.6 after 3 injections 3 days apart with the coencapsulated microparticulate formulation (MOG 17.6 μg and DXM 8 μg). This change in clinical score was significantly greater than observed with phosphate-buffered saline (PBS), empty MPs, free DXM and MOG, DXM/MPs, and MOG/MPs. Additionally, treatment with DXM/MOG/MPs significantly inhibited disease-associated cytokine (e.g., IL-17, GM-CSF) expression in splenocytes isolated in treated mice. Here we show a promising approach for the therapeutic treatment of MS using a polymer-based microparticle delivery platform.

BackgroundHeterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features.MethodsWe performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets.ResultsBased on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations.ConclusionOur findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.

Microblogs are electronic platforms that convey brief communications posted by users. Keyword searches in popular microblogs, like Twitter, reveal fragments of users' knowledge of and views on issues like climate change. Evaluations of climate change communications in the microblogosphere are rare even compared with the few studies on the impacts of Web sites and blogs on users' perceptions of climate change. However, extant research focuses more often on appraising logic and evidence in microblog discourse than in discovering pathways of influence and impact. The limiting ‘frames’ imposed by strategic users of microblogs and the persuasive power of ‘influencers’ are often depicted as interfering with the open, egalitarian potential of microblogs, and also, as perpetrating bias and misinformation. But oversimplifying or biased framings and pronouncements by celebrities are the stock and trade of microblogs. Good or bad, they are part of a communication medium whose users plunge in to exchange views, to persuade, and to be persuaded. Tweets and posts on any number of issues are fodder for attitudinal analytics and predictive modelling. Tools of the analytical trade should be applied to climate change microblogging, too, considering the sheer number of people who post commentary on this topic, and considering the continuing need to better understand how people view and engage with climate change. This article is categorized under: Perceptions, Behavior, and Communication of Climate Change > Perceptions of Climate Change

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Disease heterogeneity of immune gene expression patterns of luminal breast cancer (BC) has not been well studied. We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 Asian luminal BC patients and identified three distinct immune subtypes. Tumors in one subtype exhibited signs of T-cell activation, lower ESR1/ESR2 expression ratio and higher expression of immune checkpoint genes, nonsynonymous mutation burden, APOBEC-signature mutations, and increasing body mass index compared to other luminal tumors. Tumors in a second subtype were characterized by increased expression of interferonstimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in cases drawn from The Cancer Genome Atlas and a Korean breast cancer study. Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification.Introduction:

Acute compartment syndrome (ACS) is a serious complication of lower-extremity trauma caused by accidents or post-procedure complications. ACS is characterized by increased pressure within the compartment, resulting in reduced blood flow, tissue hypoxia, and tissue necrosis. Fasciotomies to relieve pressure and debridement of necrotic tissue comprise primary treatment. My purpose is to present initial experience using negative pressure wound therapy with instillation and dwell time (NPWTi-d)* to treat fasciotomy wounds in two patients. NPWTi-d provides automated, volumetric control of instilled topical wound solutions with a dwell time in combination with negative pressure wound therapy (NPWT).Patient 1, a 33-year-old male injured in a motorcycle accident, developed ACS within 24 hours of hospitalization. Prior treatments included wet-to-dry dressings and NPWT†. In the latter course of treatment, NPWTi-d was applied; 40 ml of normal saline (NS) were instilled with a ten-minute dwell time, followed by four hours of NPWT at ‑125 mmHg. After five days of NPWTi‑d, granulation tissue covered the bone. Four days later, the patient was discharged home. The wound continued to improve and, at the last recorded visit, was completely closed.Patient 2, a 44-year-old male, developed right lower extremity ACS due to complications post cardiac surgery. NPWT was initiated in the hospital and continued post-discharge to a nursing home. The patient was readmitted to the hospital with a right leg wound infection that was surgically debrided. NPWTi-d was then applied; 60 ml of NS were instilled with a ten-minute dwell time, followed by 3.5 hours of NPWT at -125 mmHg. After ten days of NPWTi-d, granulation tissue covered the bone. In Patient 2, NPWTi-d improved the likelihood of healing in a malnourished patient who had been critically ill by promoting granulation tissue over exposed bone. The use of NPWTi-d with NS contributed to positive outcomes for both patients.*V.A.C. VeraFlo™ Therapy, †V.A.C.® Therapy (KCI, an Acelity company, San Antonio, TX)

Age-related DNA methylation is a potential mechanism contributing to breast cancer development. Studies of primarily Caucasian women have identified many CpG sites of age-related methylation in non-diseased breast tissue possibly driving cancer development over time. There is a paucity of studies involving Asian women whose ages at breast cancer onset are usually younger than Caucasians. We identified the 181 most consistent age-related methylation events in non-diseased breast tissue across published studies. Age-related methylation events were measured in adjacent normal and breast tumour tissue in an exclusively Asian population at the previously identified age-related methylation sites. Age-related methylation was found in 118 probes in adjacent normal breast tissue. Methylation of 99% of these sites was increased with age and predominantly located on CpG islands in promoter regions. To ascertain biological relevance to breast cancer, we focused on the 37 sites with overall higher methylation in tumour compared to adjacent normal samples. Some sites positively related to age, including AQP5 and CORO6, inversely correlated with gene expression. Several others have known involvement in suppression of carcinogenesis including GPC5 and SST, suggesting that perturbation of epigenetic regulation at these sites due to ageing may contribute to the progression of carcinogenesis. This study highlights an age-related methylation landscape in non-tumour tissue, consistent not just across studies, but also across different populations. We present candidate age-related methylation sites warranting further investigation as potential epigenetic drivers of breast cancer. They may serve as potential targets of site-specific demethylation intervention strategies for the prevention of age-related breast cancer.

Summary Recent genomic studies suggest that Asian breast cancer (BC) may have distinct somatic features; however, most comparisons of BC genomic features across populations did not account for differences in age, subtype, and sequencing methods. In this study, we analyzed whole-exome sequencing (WES) data to characterize s omatic copy number alterations (SCNAs) and mutation profiles in 98 Hong Kong BC (HKBC) patients and compared with those from The Cancer Genome Atlas of European ancestry (TCGA-EA, N = 686), which had similar distributions of age at diagnosis and PAM50 subtypes as in HKBC. We developed a two-sample Poisson model to compare driver gene selection pressure, which reflects the effect sizes of cancer driver genes, while accounting for differences in sample size, sequencing platforms, depths, and mutation calling methods. We found that somatic mutation and SCNA profiles were overall very similar between HKBC and TCGA-EA. The selection pressure for small insertions and deletions (indels) in GATA3 (false discovery rate (FDR) corrected p < 0.01) and single-nucleotide variants (SNVs) in TP53 (nominal p = 0.02, FDR corrected p = 0.28) was lower in HKBC than in TCGA-EA. Among the 13 signatures of single-base substitutions (SBS) that are common in BC, we found a suggestively higher contribution of SBS18 and a lower contribution of SBS1 in HKBC than in TCGA-EA, while the two APOBEC -induced signatures showed similar prevalence . Our results suggest that the genomic landscape of BC was largely very similar between HKBC and TCGA-EA, despite suggestive differences in some driver genes and mutational signatures that warrant future investigations in large and diverse Asian populations.