Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers, does not express estrogen receptor (ER) or progesterone receptor (PR) and lacks human epidermal growth factor receptor 2 (HER2) overexpression or amplification. These tumors have a more aggressive phenotype and a poorer prognosis due to the high propensity for metastatic progression and absence of specific targeted treatments. Patients with TNBC do not benefit from hormonal or trastuzumab-based targeted therapies because of the loss of target receptors. Although these patients respond to chemotherapeutic agents such as taxanes and anthracyclines better than other subtypes of breast cancer, prognosis remains poor. A group of targeted therapies under investigation showed favorable results in TNBC, especially in cancers with BRCA mutation. The lipid-lowering statins (3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors), including lovastatin and simvastatin, have been shown to preferentially target TNBC compared with non-TNBC. These statins hold great promise for the management of TNBC. Only with the understanding of the molecular basis for the preference of statins for TNBC and more investigations in clinical trials can they be reformulated into a clinically approved drug against TNBC.

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These data suggest that chemoattractive mechanisms involve migration of cancer cells towards bone tissue, and that cell signaling induced by binding of the chemokine to its receptor leads to the activation of multiple signaling pathways and subsequent secretion of MMP-9 into the local environment. These findings provide a link between chemoattractive mechanisms, growth of tumor cells in bone, and tumor-enhanced bone matrix turnover.

Background Clinical studies have shown that resuscitation with fresh frozen plasma (FFP) is associated with improved outcome after severe hemorrhagic shock (HS). We hypothesized that in addition to its effects on hemostasis, FFP has protective and stabilizing effects on the endothelium that translate into diminished endothelial cell (EC) permeability and improved resuscitation in vivo after HS. We further hypothesized that the beneficial effects of FFP would diminish over 5 days of routine storage at 4°C. Methods EC permeability was induced by hypoxia and assessed by the passage of 70-kDa Dextran between monolayers. Thrombin generation time and coagulation factor levels or activity were assessed in FFP. An in vivo rat model of HS and resuscitation was used to determine the effects of FFP on hemodynamic stability. Results Thawed FFP inhibits EC permeability in vitro by 10.2-fold. Protective effects diminish (to 2.5-fold) by day 5. Thrombin generation time is increased in plasma that has been stored between days 0 and 5. In vivo data show that day 0 FFP is superior to day 5 FFP in maintaining mean arterial pressure in rats undergoing HS with resuscitation. Conclusion Both in vitro and in vivo studies show that FFP has beneficial effects on endothelial permeability, vascular stability, and resuscitation in rats after HS. The benefits are independent of hemostasis and diminish between days 0 and 5 of storage.

MicroRNAs (miRNAs) are highly conserved noncoding RNAs of about 19-25 nucleotides. Through specifically pairing with complementary sites in 3' untranslated regions (UTRs) of target mRNAs, they mediate post-transcriptional silencing. MicroRNAs have been implicated in many physiological processes including proliferation, differentiation, development, apoptosis, and metabolism. In recent years many studies have revealed that the aberrant expression of miRNA is closely related to oncogenesis and is now an intense field of study. Mir-148a is aberrantly expressed in various cancers and has been identified as an oncogenic or tumor suppressor with crucial roles in the molecular mechanisms of oncogenesis. In this review, we have summarized the role of mir-148a in the oncogenic pathways of gastric, liver, breast and urogenital cancers, and in neurogliocytoma oncogenesis. Studying the functional role of mir-148a is crucial in discovering novel tumor molecular markers and identifying potential therapeutic targets.

Previously, we and others showed that broad spectrum pharmaceutical inhibition of matrix metalloproteinase (MMP) activity reduces intraosseous tumor burden and bone degradation in animal models of bone metastasis. Herein, we used specific assays to measure net enzymatic activities of individual MMPs during colonization of bone by prostate cancer cells. PC3 cells were injected into the marrow of human fetal femurs previously implanted in SCID mice. Net MMP-9 activity in bone tissues peaked 2 weeks after injection, coinciding with a wave of osteoclast recruitment. In contrast, MMP-2 and MT1-MMP activity did not change. In vitro, co-culture of PC3 cells with bone tissue led to activation of pro-MMP-9 and increases in secreted net MMP-9 activity. Activation of pro-MMP-9 was prevented by metalloprotease inhibitors but not by inhibitors of other classes of proteases. Ribozyme suppression of MMP-9 expression in PC3 cells did not affect pro-MMP-9 activation or net MMP-9 activity and did not affect the phenotype of bone tumors. siRNA targeting of MMP-9 expression in preosteoclasts in vitro demonstrated that tumorinduced preosteoclast motility was dependent on MMP-9 expression. These data suggest that osteoclastderived MMP-9 may represent a potential therapeutic target in bone metastasis and provide a rationale for the development of MMP-9-specific inhibitors. Prostate cancer is the most common cancer and second leading cause of cancer death in American males.1 The overwhelming majority of prostate cancer deaths occurs in patients with metastases, and up to 90% of prostate cancer metastases occurs at skeletal sites. 2 Patients with bone metastasis frequently suffer from pain, pathological fractures, spinal cord compression, hypercalcemia, and bone marrow suppression.3,4 Although prostate cancer metastases typically appear osteosclerotic on radiographical imaging studies, multiple lines of evidence demonstrate clearly that both bone degradation and bone formation are present within the metastatic deposits. Importantly, there is now evidence that therapies that specifically target skeletal metastases, as opposed to general metastases, may extend survival in patients with prostate cancer.

Doxorubicin (DOX), also known as adriamycin, is a DNA topoisomerase II inhibitor and belongs to the family of anthracycline anticancer drugs. DOX is used for the treatment of a wide variety of cancer types. However, resistance among cancer cells has emerged as a major barrier to effective treatment using DOX. Currently, the role of autophagy in cancer resistance to DOX and the mechanisms involved have become one of the areas of intense investigation. More and more preclinical data are being obtained on reversing DOX resistance through modulation of autophagy as one of the promising therapeutic strategies. This review summarizes the recent advances in autophagy-targeting therapies that overcome DOX resistance from in-vitro studies to animal models for exploration of novel delivery systems. In-depth understanding of the mechanisms of autophagy regulation in relation to DOX resistance and development of molecularly targeted autophagy-modulating agents will provide a promising therapeutic strategy for overcoming DOX resistance in cancer treatment.

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