The Applications and Challenges of the Development of In Vitro Tumor Microenvironment Chips

The tumor microenvironment (TME) plays a critical, yet mechanistically elusive role in tumor development and progression, as well as drug resistance. To better understand the pathophysiology of the complex TME, a reductionist approach has been employed to create in vitro microfluidic models called “tumor chips”. Herein, we review the fabrication processes, applications, and limitations of the tumor chips currently under development for use in cancer research. Tumor chips afford capabilities for real-time observation, precise control of microenvironment factors (e.g. stromal and cellular components), and application of physiologically relevant fluid shear stresses and perturbations. Applications for tumor chips include drug screening and toxicity testing, assessment of drug delivery modalities, and studies of transport and interactions of immune cells and circulating tumor cells with primary tumor sites. The utility of tumor chips is currently limited by the ability to recapitulate the nuances of tumor physiology, including extracellular matrix composition and stiffness, heterogeneity of cellular components, hypoxic gradients, and inclusion of blood cells and the coagulome in the blood microenvironment. Overcoming these challenges and improving the physiological relevance of in vitro tumor models could provide powerful testing platforms in cancer research and decrease the need for animal and clinical studies

Basic science research opportunities in thrombosis and hemostasis : Communication from the SSC of the ISTH

ACKNOWLEDGMENTS We thank Drs. Hari Hara Sudhan Lakshmanan and Sven Olson for illustrative assistance and design.Peer reviewedPublisher PD

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Data detailing the platelet acetyl-lysine proteome

Here we detail proteomics data that describe the acetyl-lysine proteome of blood platelets (Aslan et al., 2015 [1]). An affinity purification – mass spectrometry (AP-MS) approach was used to identify proteins modified by Nε-lysine acetylation in quiescent, washed human platelets. The data provide insights into potential regulatory mechanisms of platelet function mediated by protein lysine acetylation. Additionally, as platelets are anucleate and lack histone proteins, they offer a unique and valuable system to study the regulation of cytosolic proteins by lysine acetylation. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (Vizcaino et al., 2014 [2]) via with PRIDE partner repository with the dataset identifier PXD002332

Chronic liver disease, thrombocytopenia and procedural bleeding risk; are novel thrombopoietin mimetics the solution?

Chronic liver disease (CLD) alters normal hemostatic and thrombotic systems via multiple mechanisms including reduced platelet function and number, leading to challenging peri-operative planning. Hepatic thrombopoietin (TPO) synthesis is reduced in CLD, leading to several recent randomized, placebo-controlled trials examining the utility of TPO-mimetics to increase platelet counts prior to surgery. While these trials do suggest that TPO-mimetics are efficacious at increasing platelet counts in patients with CLD and have led to several recent drug approvals in this space by the U.S. Food & Drug Administration, it remains unclear whether these results translate to the relevant clinical endpoint of reduced perioperative bleeding rate and severity. In this article, we review several recently-published, phase 3 trials on the TPO-mimetics eltrombopag, avatrombopag and lusutrombopag, and discuss the clinical significance of their results

Carpe low-dose aspirin: the new anti-cancer face of an old anti-platelet drug

Cancer metastasis is a dynamic process during which cancer cells separate from a primary tumor, migrate through the vessel wall into the bloodstream, and extravasate at distant sites to form secondary colonies. During this process, circulating tumor cells are subjected to shear stress forces from blood flow, and in contact with plasma proteins and blood cells of the immune and hemostatic system, including platelets. Many studies have shown an association between high platelet count and cancer metastasis, suggesting that platelets may play an occult role in tumorigenesis. This mini-review summarizes recent and emerging discoveries of mechanisms by which cancer cells activate platelets and the role of activated platelets in promoting tumor growth and metastasis. Moreover, the review discusses how aspirin has the potential for being clinically used as an adjuvant in cancer therapy

Severe thrombocytopenia in adults undergoing extracorporeal membrane oxygenation is predictive of thrombosis

Extracorporeal membrane oxygenation (ECMO) provides lifesaving circulatory support and gas exchange, although hematologic complications are frequent. The relationship between ECMO and severe thrombocytopenia (platelet count <50 × 109/L) remains ill-defined. We performed a cohort study of 67 patients who received ECMO between 2016 and 2019, of which 65.7% received veno-arterial (VA) ECMO and 34.3% received veno-venous (VV) ECMO. All patients received heparin and 25.4% received antiplatelet therapy. In total, 23.9% of patients had a thrombotic event and 67.2% had a hemorrhagic event. 38.8% of patients developed severe thrombocytopenia. Severe thrombocytopenia was more common in patients with lower baseline platelet counts and increased the likelihood of thrombosis by 365% (OR 3.65, 95% CI 1.13–11.8, P = .031), while the type of ECMO (VA or VV) was not predictive of severe thrombocytopenia (P = .764). Multivariate logistic regression controlling for additional clinical variables found that severe thrombocytopenia predicted thrombosis (OR 3.65, CI 1.13–11.78, P = .031). Over a quarter of patients requiring ECMO developed severe thrombocytopenia in our cohort, which was associated with an increased risk of thrombosis and in-hospital mortality. Additional prospective observation is required to clarify the clinical implications of severe thrombocytopenia in the ECMO patient population