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Cancer chemoprevention is a new approach in the management of cancer. Traditional cytotoxic chemotherapeutic approaches cannot cure most advanced solid malignancies. Chemoprevention can be defined as the use of non-cytotoxic drugs and natural agents to block the progression to invasive cancer. Chemoprevention can either prevent DNA damage that initiates the neoplastic transformation process or reverses the progression of pre-invasive lesions. Epidemiological observations, experimental evidence from animal carcinogenesis models, knock-out models, cancer cell lines and clinical trials have shown the efficacy of this approach. Recent advances in our understanding of carcinogenesis have led to the synthesis of new drugs that target specific receptors. Non-steroidal anti-inflammatory drugs target the prostaglandin pathway. The identification of the role of cyclooxygenase-2 in epithelial carcinogenesis led to the synthesis of selective cyclooxygenase-2 inhibitors (Celecoxib). Celecoxib was subsequently approved for the prevention of colon polyps in familial adenomatous polyposis after the completion of a randomized clinical trial. The large chemoprevention clinical trial with the selective estrogen receptor modulator, tamoxifen, showed the benefit of tamoxifen in the prevention of breast cancer in high-risk women. Retinoids and rexinoids target the retinoid receptors and have a role in chemoprevention of aerodigestive, hepatic and cervical neoplasia. Selenium, an inhibitor of the glutathione peroxidase system, is being tested in the chemoprevention of prostate cancer and lung cancer. The different isoforms of vitamin E (tocopherols) may be chemopreventive. Recent evidence indicates that γ-tocopherol may be a more powerful chemopreventive than the α-tocopherol. The review details the rationale, experimental and clinical evidence and the drug targets of the chemopreventive agents that are currently in various phases of clinical development.

In this study, we demonstrate that killer cell lectin-like receptor subfamily G member 1 (KLRG1), a transmembrane protein preferentially expressed on T cells, is highly expressed on CD56+ NK cells, which are significantly reduced in their numbers and functions in the peripheral blood of patients with chronic hepatitis C virus (HCV) infection compared to subjects without infection. KLRG1 expression is also upregulated on healthy NK cells exposed to Huh-7 hepatocytes infected with HCV in vitro. Importantly, the expression levels of KLRG1 are inversely associated with the capacity of NK cells to proliferate and to produce gamma interferon (IFN-γ) but positively associated with apoptosis of NK cells in response to inflammatory cytokine stimulation. KLRG1- NK cells, including CD56bright and CD56dim subsets, exhibit impaired cell activation and IFN-γ production but increased apoptosis compared to KLRG1- NK cells, particularly in HCV-infected individuals. Importantly, blockade of KLRG1 signaling significantly recovered the impaired IFN-γ production by NK cells from HCV-infected subjects. Blockade of KLRG1 also enhanced the impaired phosphorylation of Akt (Ser473) in NK cells from HCV-infected subjects. Taken together, these results indicate that KLRG1 negatively regulates NK cell numbers and functions via the Akt pathway, thus providing a novel marker and therapeutic target for HCV infection.

The purpose of this meta-analysis was to compare postprocedural mortality and major adverse cardiovascular and cerebrovascular events between transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) for severe aortic stenosis. Seventeen studies (n = 4,659) comparing TAVI (n = 2,267) and SAVR (n = 2,392) were included. End points were baseline logistic European System for Cardiac Operative Risk Evaluation score, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, transient ischemic attack, and major bleeding events. Mean differences or risk ratios with 95% confidence intervals were computed, and p values <0.05 were considered significant. The population was matched for risk between the 2 groups on the basis of logistic European System for Cardiac Operative Risk Evaluation score for all outcomes except 30-day all-cause mortality, which had a high-risk population in the TAVI group (p = 0.02). There was no significant difference found in all-cause mortality at 30 days (p=0.97) and at an average of 85 weeks (p=0.07). There was no significant difference in cardiovascular mortality (p=0.54) as well as the incidence of myocardial infarction (p=0.59), stroke (p=0.36), and transient ischemic attack (p = 0.85) at averages of 86, 72, 66, and 89 weeks, respectively. Compared with patients who underwent TAVI, those who underwent SAVR had a significantly higher frequency of major bleeding events (p <0.0001) at mean follow-up of 66 weeks. In conclusion, TAVI has similar cardiovascular and all-cause mortality to SAVR at early and long-term follow-up. TAVI is superior to SAVR for major bleeding complications and noninferior to SAVR for postprocedural myocardial infarctions and cerebrovascular events. TAVI is a safe alternative to SAVR in selected high-risk elderly patients with severe aortic stenosis.

Human monocytes/macrophages (M/MΦ) of the innate immunity sense and respond to microbial products via specific receptor coupling with stimulatory (such as TLR) and inhibitory (such as Tim-3) receptors. Current models imply that Tim-3 expression on M/MØ can deliver negative signaling to TLR-mediated IL-12 expression through trans association with its ligand Galectin-9 (Gal-9) presented by other cells. However, Gal-9 is also expressed within M/MØ, and the effect of intracellular Gal-9 on Tim-3 activities and inflammatory responses in the same M/MØ remains unknown. In this study, our data suggest that Tim-3 and IL-12/IL-23 gene transcriptions are regulated by enhanced or silenced Gal-9 expression within monocytes through synergizing with TLR signaling. Additionally, TLR activation facilitates Gal-9/Tim-3 cis association within the same M/MØ to differentially regulate IL-12/IL-23 expressions through STAT-3 phosphorylation. These results reveal a ligand (Gal-9) compartment-dependent regulatory effect on receptor (Tim-3) activities and inflammatory responses via TLR pathways-a novel mechanism underlying cellular responses to external or internal cues.

Drug-resistant gonorrhea, Neisseria gonorrhoeae (N. gonorrhoeae), is an emerging concern, especially because the risk of bladder cancer is associated with this infection. N. gonorrhoeae suppresses T-helper 1(Th1) and Th2 responses and enhances Th17 responses via a mechanism involving transforming growth factor-beta (TGF-β) and regulatory T cells. Blockade of TGF-β alleviates the suppression of specific anti-gonococcal responses and allows Th1 and Th2 responses to emerge with concomitant boosting of immune memory and protective immunity. Gonorrhea activates nuclear factor kappaB (NF-kappaB), which plays a critical role in signal-transduction pathways involved in inflammation. The innate immune system can eventually clear gonorrhea. Vitamin D is emerging as a potential, powerful, anti-microbial agent with these effects: it supports the innate immune system in combating bacterial infections; it decreases levels of TGF-β and NF-kappaB activation; and it induces production of LL-37 (cathelicidin), which has antimicrobial and antiendotoxin properties. In addition, via an independent vitamin D receptor pathway, curcumin also induces LL-37 production, inhibiting N. gonorrhoeae-induced NF-kappaB signaling and inducing autophagy. Therefore, vitamin D and curcumin taken together may be useful in combating both normal and drug-resistant gonorrhea. Moreover, the possible synergy between these two agents in improving outcomes is worthy of additional investigation.