Cancer cell immunity-related protein co-expression networks are associated with early-stage solid-predominant lung adenocarcinoma

BackgroundSolid-predominant lung adenocarcinoma (SPA), which is one of the high-risk subtypes with poor prognosis and unsatisfactory response to chemotherapy and targeted therapy in lung adenocarcinoma, remains molecular profile unclarified. Weighted correlation network analysis (WGCNA) was used for data mining, especially for studying biological networks based on pairwise correlations between variables. This study aimed to identify disease-related protein co-expression networks associated with early-stage SPA.MethodsWe assessed cancerous cells laser-microdissected from formalin-fixed paraffin-embedded (FFPE) tissues of a SPA group (n = 5), referencing a low-risk subtype, a lepidic predominant subtype group (LPA) (n = 4), and another high-risk subtype, micropapillary predominant subtype (MPA) group (n = 3) and performed mass spectrometry-based proteomic analysis. Disease-related co-expression networks associated with the SPA subtype were identified by WGCNA and their upstream regulators and causal networks were predicted by Ingenuity Pathway Analysis.ResultsAmong the forty WGCNA network modules identified, two network modules were found to be associated significantly with the SPA subtype. Canonical enriched pathways were highly associated with cellular growth, proliferation, and immune response. Upregulated HLA class I molecules HLA-G and HLA-B implicated high mutation burden and T cell activation in the SPA subtype. Upstream analysis implicated the involvement of highly activated oncogenic regulators, MYC, MLXIPL, MYCN, the redox master regulator NFE2L2, and the highly inhibited LARP1, leading to oncogenic IRES-dependent translation, and also regulators of the adaptive immune response, including highly activated IFNG, TCRD, CD3-TCR, CD8A, CD8B, CD3, CD80/CD86, and highly inhibited LILRB2. Interestingly, the immune checkpoint molecule HLA-G, which is the counterpart of LILRB2, was highly expressed characteristically in the SPA subtype and might be associated with antitumor immunity.ConclusionOur findings provide a disease molecular profile based on protein co-expression networks identified for the high-risk solid predominant adenocarcinoma, which will help develop future therapeutic strategies

Refractory lung metastasis from breast cancer treated with multidisciplinary therapy including an immunological approach.

A suggestive case of metastatic disease from breast cancer is reported. The HER-2-positive tumor was refractory to several agents, including anti-HER-2 therapy, trastuzumab, and lapatinib. After re-induction of trastuzumab in combination with activated natural killer (NK) cell injection therapy, tumor markers decreased, and finally a synergistic effect of taxane and capecitabine led to treatment response. This case suggests that multidisciplinary therapy including an immunological approach might be a breakthrough in the treatment of refractory disease

Location of the Susceptibility Vessel Sign on T2*-Weighted MRI and Early Recanalization within 1 Hour after Tissue Plasminogen Activator Administration

Background: We have recently reported that the susceptibility vessel sign (SVS) at the proximal portion of the horizontal (M1) middle cerebral artery (MCA) on T2*-weighted MRI is a strong predictor for no early recanalization after intravenous recombinant tissue plasminogen activator (t-PA) therapy. However, it is unclear whether the presence of the SVS at other locations, such as distal M1, the vertical portion (M2) of the MCA, and distal branches (MCA distal), is a predictor for no early recanalization in acute ischemic stroke patients. Methods: The SVS was defined as a hypointense signal of the MCA on T2*-weighted MRI on admission. The locations of the SVS were classified as M1 proximal, M1 distal, and MCA distal. M1 proximal SVS was defined as an SVS at the origin of the M1. M1 distal SVS was any M1 SVS not including the origin of the M1. MCA distal SVS was an SVS further away from M1. Early recanalization was defined as a new appearance of at least one of the distal branches on MRA within 1 h after t-PA therapy. A good outcome at 3 months was defined as a modified Rankin Scale (mRS) score of 0-1. Results: Consecutive acute stroke patients admitted to our stroke center and treated with t-PA between October 2005 and October 2012 were enrolled. There were 158 patients [median age, 78 (71-84) years; 84 (53%) males; median National Institutes of Health Stroke Scale score, 16 (10-20)]. Internal carotid artery occlusion was seen in 18 (72%) of the 25 patients with M1 proximal SVS, in 3 (14%) of the 22 patients with M1 distal SVS, in 4 (9%) of the 44 patients with MCA distal SVS, and in 18 (27%) of the 67 patients with No SVS (p Conclusion: M1 proximal SVS on T2*-weighted MRI is a strong predictor for no early recanalization, and all patients with it had a poor outcome. However, M1 distal SVS and MCA distal SVS were not predictors for no early recanalization, and half of the patients had a poor outcome

Norepinephrine Transporter Imaging in the Brain of a Rat Model of Depression Using Radioiodinated (2S, αS)-2-(α-(2-iodophenoxy)benzyl)morpholine

To visualize the norepinephrine transporters (NETs) in various brain diseases, we developed radioiodinated (2S,αS)-2-(α-(2-iodophenoxy)benzyl)morpholine ((S,S)-IPBM). This radioligand achieved the basic requirements for NET imaging. In this study, we assessed the potential of radioiodinated (S,S)-IPBM as an imaging biomarker of NET to obtain diagnostic information about depression in relation to NET expression in the brain using a rat depression model. The ex vivo autoradiographic experiments using the (S,S)-[ 125 I]IPBM showed significantly lower accumulation of radioactivity in the locus coeruleus (LC) and the anteroventricular thalamic nucleus (AVTN) of the depression group than in those of the control group. Consequently, in vitro autoradiographic experiments showed that NET maximum binding (B max ) values in the LC and AVTN, known as NET-rich regions, were significantly decreased in the rat model of depression when compared to those of the control rats. In addition, there was an extremely good correlation between NET B max and (S,S)-IPBM accumulation ( r = .98), an indication of radioiodinated IPBM as a quantitative NET imaging biomarker. The reduction in(S,S)-[ 125 I]IPBM accumulation in the rat model of depression correlated with that of NET density. These results suggest that (S,S)-[ 123 I]IPBM has potential as an imaging biomarker of NET to obtain diagnostic information about major depression

Current status of clinical proteogenomics in lung cancer

Introduction: Lung cancer is the leading cause of cancer death worldwide. Proteogenomics, a way to integrate genomics, transcriptomics, and proteomics, have emerged as a way to understand molecular causes in cancer tumorigenesis. This understanding will help identify therapeutic targets that are urgently needed to improve individual patient outcomes. Areas covered: To explore underlying molecular mechanisms of lung cancer subtypes, several efforts have used proteogenomic approaches that integrate next generation sequencing (NGS) and mass spectrometry (MS)-based technologies. Expert opinion: A large-scale, MS-based, proteomic analysis, together with both NGS-based genomic data and clinicopathological information, will facilitate establishing extensive databases for lung cancer subtypes that can be used for further proteogenomic analyzes. Proteogenomic strategies will further be understanding of how major driver mutations affect downstream molecular networks, resulting in lung cancer progression and malignancy, and how therapy-resistant cancers resistant are molecularly structured. These strategies require advanced bioinformatics based on a dynamic theory of network systems, rather than statistics, to accurately identify mutant proteins and their affected key networks

Re-evaluation of Clinical Features and Risk Factors of Acute Ischemic Stroke in Japanese Longevity Society

Age is an important factor correlated with stroke prevalence and independently influences stroke outcome especially in Japanese longevity society. To re-evaluate the characteristics of acute ischemic stroke in the old-old, analyses of clinical data on 426 patients registered at a Japanese tertiary emergency hospital were performed under appropriate statistical methods. Clinical features, stroke subtypes, current-known risk factors for stroke, time from onset to arrival, the National Institute of Health Stroke scale (NIHSS) score on admission, length of hospital stay, modified Rankin Scale (mRS) at discharge were compared between two stratified groups by age-at-onset (≧75 and < 75 years old). Significant differences were demonstrated in categories of sex, NIHSS score, length of hospital stay and m-RS. Current-known risk factors for stroke except atrial fibrillation were not prominent in the elderly group. Our study revealed that clinical phenotype and outcome in stroke patients would have been modified and re-evaluation of risk factors is necessary for prevention of ischemic stroke in Japanese longevity society