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Background About 45% of the human genome is comprised of mobile transposable elements or \"junk DNA\". The exaptation or co-option of these elements to provide important cellular functions is hypothesized to have played a powerful force in evolution; however, proven examples are rare. An ancient primate-specific Alu short interspersed element (SINE) put the human CAMP gene under the regulation of the vitamin D pathway by providing a perfect vitamin D receptor binding element (VDRE) in its promoter. Subsequent studies demonstrated that the vitamin D-cathelicidin pathway may be a key component of a novel innate immune response of human to infection. The lack of evolutionary conservation in non-primate mammals suggested that this is a primate-specific adaptation. Evidence for evolutionary conservation of this regulation in additional primate lineages would provide strong evidence that the TLR2/1-vitamin D-cathelicidin pathway evolved as a biologically important immune response mechanism protecting human and non-human primates against infection. Results PCR-based amplification of the Alu SINE from human and non-human primate genomic DNA and subsequent sequence analysis, revealed perfect structural conservation of the VDRE in all primates examined. Reporter gene studies and induction of the endogenous CAMP gene in Rhesus macaque peripheral blood mononuclear cells demonstrated that the VDREs were conserved functionally. In addition, New World monkeys (NWMs) have maintained additional, functional steroid-hormone receptor binding sites in the AluSx SINE that confer retinoic acid responsiveness and provide potential thyroid hormone receptor binding sites. These sites were less well-conserved during human, ape and Old World monkey (OWM) evolution and the human CAMP gene does not respond to either retinoic acid or thyroid hormone. Conclusion We demonstrated that the VDRE in the CAMP gene originated from the exaptation of an AluSx SINE in the lineage leading to humans, apes, OWMs and NWMs and remained under purifying selection for the last 55–60 million years. We present convincing evidence of an evolutionarily fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals. Evolutionary selection to place the primate CAMP gene under regulation of the vitamin D pathway potentiates the innate immune response and may counter the anti-inflammatory properties of vitamin D.

Proteasome inhibitor PS‐341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of NF‐κB in vitro and has afforded some objective responses in individuals with relapsed, refractory MM. However, the activity of PS‐341 against non‐hematological malignancies remains to be fully elucidated. In this study, we found that PS‐341 induced growth arrest and apoptosis of NCI‐H520 and ‐H460 non‐small cell lung cancer (NSCLC) cells in conjunction with markedly up‐regulated levels of p21waf1 and p53, and down‐regulation of bcl‐2 protein in these cells. Also, PS‐341 caused phosphorylation of c‐Jun NH2‐terminal kinase (JNK) and c‐Jun, and enhanced AP‐1/DNA binding activities in these cells as measured by western blotting and enzyme‐linked immunosorbent assay (ELISA), respectively. Interestingly, when the JNK/ c‐Jun/AP‐1 signal pathway was disrupted by the JNK inhibitor SP600125, the ability of PS‐341 to inhibit the growth of NSCLC cells and to up‐regulate the levels of p21waf1 in these cells was blunted, but the expression of p53 was sustained at a high level, suggesting that the JNK/c‐Jun/AP‐1 signal pathway might mediate the anti‐lung cancer effects of PS‐341, with p21waf1 playing the central role. Thus, PS‐341 might be useful for the treatment of individuals with NSCLC.

Proteasome inhibitor PS‐341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of nuclear factor KB (NF‐KB) in vitro. In addition, recent clinical studies of PS‐341 have demonstrated some objective responses in individuals with relapsed, refractory MM. However, the activity of PS‐341 against non‐hematological malignancies remains to be fully elucidated. In this study, we found that PS‐341 induced growth arrest and apoptosis of androgen‐dependent human prostate cancer LNCaP cells in conjunction with markedly up‐regulated levels of p21waf1 and p53. In addition, we found that PS‐341 down‐regulated both 5α dihydrotestosterone (DHT)‐ and interleukin‐6 (IL‐6)‐induced expression of prostate‐specific antigen (PSA) as measured by western blot analysis. PS‐341 down‐regulated basal levels of the androgen receptor (AR) in the nucleus; however, it did not affect DHT‐induced nuclear translocation of AR in these cells. Reporter assays using a series of promoters of the PSA gene showed that down‐regulation of PSA by PS‐341 was caused by inhibition of the transcriptional activity of the androgen receptor response element (ARE) in these cells. Taken together, the results indicate that PS‐341 induced growth arrest and apoptosis of LNCaP cells by blockade of the AR signaling pathway. The proteasome may be a molecular target for treatment of a variety of cancers including prostate cancer.

Abstract We report a case of systemic lupus erythematosus that concomitantly occurred with autoimmune pancreatitis. The clinical manifestations of pancreatitis improved in response to steroid therapy. Although the pathogenesis of autoimmune pancreatitis is still controversial, as is that of systemic lupus erythematosus, the observations in the present case suggest the presence of an autoimmune mechanism underlying autoimmune pancreatitis.

We report a case of systemic lupus erythematosus that concomitantly occurred with autoimmune pancreatitis. The clinical manifestations of pancreatitis improved in response to steroid therapy. Although the pathogenesis of autoimmune pancreatitis is still controversial, as is that of systemic lupus erythematosus, the observations in the present case suggest the presence of an autoimmune mechanism underlying autoimmune pancreatitis. [PUBLICATION ABSTRACT]

We report a case of systemic lupus erythematosus that concomitantly occurred with autoimmune pancreatitis. The clinical manifestations of pancreatitis improved in response to steroid therapy. Although the pathogenesis of autoimmune pancreatitis is still controversial, as is that of systemic lupus erythematosus, the observations in the present case suggest the presence of an autoimmune mechanism underlying autoimmune pancreatitis.