Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies

The translation of in vitro findings to clinical outcomes is often elusive. Trauma/hemorrhagic shock (T/HS) results in hepatic hypoxia that drives inflammation. We hypothesize that in silico methods would help bridge in vitro hepatocyte data and clinical T/HS, in which the liver is a primary site of inflammation. Primary mouse hepatocytes were cultured under hypoxia (1% O 2) or normoxia (21% O2) for 1-72 h, and both the cell supernatants and protein lysates were assayed for 18 inflammatory mediators by Luminex™ technology. Statistical analysis and data-driven modeling were employed to characterize the main components of the cellular response. Statistical analyses, hierarchical and k-means clustering, Principal Component Analysis, and Dynamic Network Analysis suggested MCP-1/CCL2 and IL-1α as central coordinators of hepatocyte-mediated inflammation in C57BL/6 mouse hepatocytes. Hepatocytes from MCP-1-null mice had altered dynamic inflammatory networks. Circulating MCP-1 levels segregated human T/HS survivors from non-survivors. Furthermore, T/HS survivors with elevated early levels of plasma MCP-1 post-injury had longer total lengths of stay, longer intensive care unit lengths of stay, and prolonged requirement for mechanical ventilation vs. those with low plasma MCP-1. This study identifies MCP-1 as a main driver of the response of hepatocytes in vitro and as a biomarker for clinical outcomes in T/HS, and suggests an experimental and computational framework for discovery of novel clinical biomarkers in inflammatory diseases. © 2013 Ziraldo et al

Factors that predict early treatment failure for patients with locally advanced (T4) breast cancer

Locally advanced breast cancer (LABC) is associated with dire prognosis despite progress in multimodal treatments. We evaluated several clinical and pathological features of patients with either noninflammatory (NIBC, cT4a-c) or inflammatory (IBC, cT4d) breast cancer to identify subset groups of patients with high risk of early treatment failure. Clinical and pathological features of 248 patients with LABC, who were treated with multimodality treatments including neoadjuvant chemotherapy followed by radical surgery and radiotherapy were reassessed. Tumour samples obtained at surgery were evaluated using standard immunohistochemical methods. Overall, 141 patients (57%) presented with NIBC (cT4a-c, N0-2, M0) and 107 patients (43%) with IBC (cT4d, N0-2, M0). Median follow-up time was 27.5 months (range: 1.6–87.8). No significant difference in terms of recurrence-free survival (RFS) (P=0.72), disease-free survival (DFS) (P=0.98) and overall survival (OS) (P=0.35) was observed between NIBC and IBC. At the multivariate analysis, patients with ER- and PgR-negative diseases had a significantly worse RFS than patients with ER- and/or PgR-positive diseases (hazard ratio: 2.47, 95% CI: 1.33–4.59 for overall). The worst RFS was observed for the subgroup of patients with endocrine nonresponsive and HER2-negative breast cancer (2-year RFS: 57% in NIBC and 57% in IBC) A high Ki-67 labelling index (>20% of the invasive tumour cells) and the presence of peritumoral vascular invasion (PVI) significantly correlated with poorer RFS in overall (HR 2.69, 95% CI: 1.61–4.50 for Ki-67>20% and HR 2.27, 95% CI: 1.42–3.62 for PVI). Patients with endocrine nonresponsive LABC had the most dire treatment outcome. High degree of Ki-67 staining and presence of PVI were also indicators of higher risk of early relapse. These factors should be considered in therapeutic algorithms for LABC

Functional proteomics can define prognosis and predict pathologic complete response in patients with breast cancer

<p>Abstract</p> <p>Purpose</p> <p>To determine whether functional proteomics improves breast cancer classification and prognostication and can predict pathological complete response (pCR) in patients receiving neoadjuvant taxane and anthracycline-taxane-based systemic therapy (NST).</p> <p>Methods</p> <p>Reverse phase protein array (RPPA) using 146 antibodies to proteins relevant to breast cancer was applied to three independent tumor sets. Supervised clustering to identify subgroups and prognosis in surgical excision specimens from a training set (n = 712) was validated on a test set (n = 168) in two cohorts of patients with primary breast cancer. A score was constructed using ordinal logistic regression to quantify the probability of recurrence in the training set and tested in the test set. The score was then evaluated on 132 FNA biopsies of patients treated with NST to determine ability to predict pCR.</p> <p>Results</p> <p>Six breast cancer subgroups were identified by a 10-protein biomarker panel in the 712 tumor training set. They were associated with different recurrence-free survival (RFS) (log-rank p = 8.8 E-10). The structure and ability of the six subgroups to predict RFS was confirmed in the test set (log-rank p = 0.0013). A prognosis score constructed using the 10 proteins in the training set was associated with RFS in both training and test sets (p = 3.2E-13, for test set). There was a significant association between the prognostic score and likelihood of pCR to NST in the FNA set (p = 0.0021).</p> <p>Conclusion</p> <p>We developed a 10-protein biomarker panel that classifies breast cancer into prognostic groups that may have potential utility in the management of patients who receive anthracycline-taxane-based NST.</p

Gas generation and wind power: A review of unlikely allies in the United Kingdom and Ireland

No single solution currently exists to achieve the utopian desire of zero fossil fuel electricity generation. Until such time, it is evident that the energy mix will contain a large variation in stochastic and intermittent sources of renewable energy such as wind power. The increasing prominence of wind power in pursuit of legally binding European energy targets enables policy makers and conventional generating companies to plan for the unique challenges such a natural resource presents. This drive for wind has been highly beneficial in terms of security of energy supply and reducing greenhouse gas emissions. However, it has created an unusual ally in natural gas. This paper outlines the suitability and challenges faced by gas generating units in their utilisation as key assets for renewable energy integration and the transition to a low carbon future. The Single Electricity Market of the Republic of Ireland and Northern Ireland and the British Electricity Transmission Trading Agreement Market are the backdrop to this analysis. Both of these energy markets have a reliance on gas generation matching the proliferation of wind power. The unlikely and mostly ignored relationship between natural gas generation and wind power due to policy decisions and market forces is the necessity of gas to act as a bridging fuel. This review finds gas generation to be crucially important to the continued growth of renewable energy. Additionally, it is suggested that power market design should adequately reward the flexibility required to securely operate a power system with high penetrations of renewable energy, which in most cases is provided by gas generation

Renal amyloidosis in children

Renal amyloidosis is a detrimental disease caused by the deposition of amyloid fibrils. A child with renal amyloidosis may present with proteinuria or nephrotic syndrome. Chronic renal failure may follow. Amyloid fibrils may deposit in other organs as well. The diagnosis is through the typical appearance on histopathology. Although chronic infections and chronic inflammatory diseases used to be the causes of secondary amyloidosis in children, the most frequent cause is now autoinflammatory diseases. Among this group of diseases, the most frequent one throughout the world is familial Mediterranean fever (FMF). FMF is typically characterized by attacks of clinical inflammation in the form of fever and serositis and high acute-phase reactants. Persisting inflammation in inadequately treated disease is associated with the development of secondary amyloidosis. The main treatment is colchicine. A number of other monogenic autoinflammatory diseases have also been identified. Among them cryopyrin-associated periodic syndrome (CAPS) is outstanding with its clinical features and the predilection to develop secondary amyloidosis in untreated cases. The treatment of secondary amyloidosis mainly depends on the treatment of the disease. However, a number of new treatments for amyloid per se are in the pipeline

Regulation of GSK-3 Activity as A Shared Mechanism in Psychiatric Disorders

Serin/Treonin kinaz ailesinin üyelerinden bir kinaz olarak ilk kez glikojen sentaz’ı inhibe ettiği keşfedilen glikojen sentaz kinaz-3 (GSK-3), günümüzde bilinen 50’den fazla substratı ile birçok hücre içi düzenleyici mekanizmada görev alan geniş etki spektrumlu bir enzim olarak kabul edilmektedir. GSK-3’ün memelilerde GSK-3α ve GSK-3β olmak üzere yapısal olarak yüksek homoloji gösteren iki izoformu bulunmaktadır. Her iki izoform birçok dokuda yaygın dağılım göstermekle beraber, en yüksek oranda beyinde bulunmakta ve genellikle benzer fonksiyonlar göstermektedirler. Diğer protein kinazların aksine GSK-3 uyarılmamış hücrede yapısal olarak aktif yani defosforile halde bulur. Protein kinaz A (PKA), protein kinaz B (PKB;AKT) ve protein kinaz C (PKC) gibi diğer protein kinazlarla fosforilasyona uğrayarak olarak inaktive edilir. Günümüzde artmış GSK-3 aktivitesinin major depresyon, bipolar bozukluk, hiperaktivite bozuklukları gibi hastalıklar ve şizofreni oluşumunda rol oynayabileceğine ilişkin önemli bulgular mevcuttur. Bu nedenle söz konusu psikiyatrik hastalıklarda arttığı gösterilen GSK-3 aktivitesinin azaltılmasının tedavide umut verici bir yaklaşım olabileceği kabul edilebilir. Bu gözden geçirme çalışmasında yukarıda sözü edilen psikiyatrik hastalıkların oluşmasında görev alan GSK-3 aracılı mekanizmalara kısaca değinilerek GSK-3’ün aktivitesinin düzenlenmesinde rol oynadığı gösterilen klinikte kullanılan ilaçlara yer verilmiştir. Anahtar sözcükler: GSK-3, depresyon, bipolar bozukluk, şizofren