Signaling through the second messengers calcium and diacylglycerol (DAG) is a critical element in many biological systems. Integration of calcium and DAG signals has been suggested to occur primarily through protein kinase C family members, which bind both calcium and DAG. However, an alternative pathway may involve members of the CalDAG-GEF/RasGRP protein family, which have structural features (calcium-binding EF hands and DAG-binding C1 domains) that suggest they can function in calcium and DAG signal integration. To gain insight into the signaling systems that may be regulated by CalDAG-GEF/RasGRP family members, we have focused on CalDAG-GEFI, which is expressed preferentially in the brain and blood. Through genetic ablation in the mouse, we have found that CalDAG-GEFI is crucial for signal integration in platelets. Mouse platelets that lack CalDAG-GEFI are severely compromised in integrin-dependent aggregation as a consequence of their inability to signal through CalDAG-GEFI to its target, the small GTPase Rap1. These results suggest that analogous signaling defects are likely to occur in the central nervous system when CalDAG-GEFI is absent or compromised in function.

Abstract:The injected fluids in secondary processes supplement the natural energy present in the reservoir to displace oil. The recovery efficiency mainly depends on the mechanism of pressure maintenance. However, the injected fluids in tertiary or enhanced oil recovery (EOR) processes interact with the reservoir rock/oil system. Thus, EOR techniques are receiving substantial attention worldwide as the available oil resources are declining. However, some challenges, such as low sweep efficiency, high costs and potential formation damage, still hinder the further application of these EOR technologies. Current studies on nanoparticles are seen as potential solutions to most of the challenges associated with these traditional EOR techniques. This paper provides an overview of the latest studies about the use of nanoparticles to enhance oil recovery and paves the way for researchers who are interested in the integration of these progresses. The first part of this paper addresses studies about the major EOR mechanisms of nanoparticles used in the forms of nanofluids, nanoemulsions and nanocatalysts, including disjoining pressure, viscosity increase of injection fluids, preventing asphaltene precipitation, wettability alteration and interfacial tension reduction. This part is followed by a review of the most important research regarding various novel nano-assisted EOR methods where nanoparticles are used to target various existing thermal, chemical and gas methods. Finally, this review identifies the challenges and opportunities for future study regarding application of nanoparticles in EOR processes.

Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1b, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.Cancer Res; 75(13); 2653-62. Ó2015 AACR.

The safe and efficient delivery of chemotherapeutic agents remains critical to anticancer therapy. Herein, we report on a targeted drug delivery system based upon a modified cell membrane coating technique and drug nanocrystals (NCs). Specifically, red blood cell (RBC) membrane was modified with targeting peptides through a facile insertion method involving avidin−biotin interactions. The RBC membrane-coated drug NCs (RBC-NCs) exhibited high drug loading, long-term stability, excellent biocompatibility, and prolonged retention time, all of which make them suitable for effective drug delivery. When modified with the tumor-targeting peptide c(RGDyK), the resulting RGD-RBC-NCs showed superior tumor accumulation and therapeutic efficacy both in mice bearing a subcutaneous tumor as well as orthotropic glioma. RBC-NC therapeutics can be readily generalized to the delivery of various drugs and for the treatment of a wide range of cancers.

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Background and Aims: Combining anti-angiogenic therapy with immune checkpoint blockade with anti-programmed cell death-1 (PD-1) antibodies is a promising treatment for hepatocellular carcinoma (HCC). Tyrosine kinase inhibitors are well-known anti-angiogenic agents and offer potential for combination with anti-PD-1 antibodies. This study investigated the

A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. One example is acute renal failure, a major cause of morbidity and mortality in cancer patients. Surprisingly, however, little is known about the situation in organs that are not targets for metastasis or affected by the primary tumor. Recently, neutrophil extracellular traps (NET) were implicated in tumor-induced effects on distant organs unaffected by the actual tumor cells. Formation of NETs (NETosis) was identified a decade ago as a mechanism by which the innate immune system protects us from infections, especially in situations with sepsis. NETs are formed when neutrophils externalize their nuclear DNA together with antimicrobial granule proteins and form a web-like structure that can trap and kill microbes. It is now becoming increasingly clear that NETs also form under noninfectious inflammatory conditions like cancer, thrombosis, autoimmunity, and diabetes and significantly contribute to disease development. The existence of NETdissolving drugs like heparin and DNase I, already in clinical use, and recent development of specific inhibitors of proteinarginine deiminase 4 (PAD4), an enzyme required for NET formation, should enable clinical targeting of NETosis. Preventing NETosis in cancer could provide a strategy to counteract tumor-induced thrombosis and organ failure as well as to suppress metastasis. Cancer Res; 76(15); 4311-5. Ó2016 AACR. Systemic Effects of CancerTumor-induced systemic effects are the cause of nearly all cancer-related mortalities. If the disease remains local, the patient can often be cured by surgical removal of the primary tumor. If the malignancy is allowed to develop into systemic disease, the prognosis is usually worse. Metastatic disease, that is, systemic dissemination and formation of secondary tumors in distant organs, is responsible for more than 90% of cancerrelated deaths. However, tumor-induced systemic effects can also induce pathologies that do not directly involve tumor cells. It was reported already in the mid-19th century that cancer patients suffer from increased risk for thrombosis (1). A major reason behind this observation is the capacity of tumors to induce platelet activation-a phenomenon that is not only responsible for cancer-associated thrombosis but also contributes to enhanced metastasis in several ways (2). Thrombosis is a major cause of mortality in cancer patients and hence constitutes an important clinical issue (3). Another common systemic complication of cancer is organ failure, which also involves organs not directly affected by the actual tumor growth. For example, two large studies performed during the last decade revealed that more than 50% of the cancer patients suffer from decreased renal function (4, 5). Renal dysfunction is not only a direct risk factor for mortality, but also contributes to increased risk for nephrotoxic effects upon chemotherapeutic treatment (6). Renal failure, caused by ischemia, is characterized by hypoperfusion of t...