Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism

Akt/mammalian target of rapamycin (mTOR) signaling plays an important role in tumorigenesis and is dysregulated in many tumors, especially metastatic prostate cancers. Curcumin has been shown to effectively prevent or inhibit prostate cancer in vivo and inhibit Akt/mTOR signaling in vitro, but the mechanism(s) remains unclear. Here, we show that curcumin concentration- and time-dependently inhibited the phosphorylation of Akt, mTOR, and their downstream substrates in human prostate cancer PC-3 cells, and this inhibitory effect acts downstream of phosphatidylinositol 3-kinase and phosphatidylinositol-dependent kinase 1. Overexpression of constitutively activated Akt or disruption of TSC1-TSC2 complex by small interfering RNA or gene knockout only partially restored curcumin-mediated inhibition of mTOR and downstream signaling, indicating that they are not the primary effectors of curcumin-mediated inhibition of Akt/mTOR signaling. Curcumin also activated 5'-AMP-activated protein kinase and mitogen-activated protein kinases; however, inhibition of these kinases failed to rescue the inhibition by curcumin. Finally, it was shown that the inhibition of Akt/mTOR signaling by curcumin is resulted from calyculin A-sensitive protein phosphatase-dependent dephosphorylation. Our study reveals the profound effects of curcumin on the Akt/mTOR signaling network in PC-3 cells and provides new mechanisms for the anticancer effects of curcumin. [Mol Cancer Ther 2008;7(9):2609-20].     

Detection of group B rotavirus in an adult with acute gastroenteritis in Yangon,Myanmar

In Yangon, Myanmar, a human group B rotavirus was first detected in 2007 in a stool specimen from a sporadic case of acute gastroenteritis in an adult. The strain was designated as MMR‐B1. The full‐length sequences of the MMR‐B1 genes encoding VP7, VP4 (VP5* and VP8*), VP6, and NSP4 were determined for genetic characterization. These four MMR‐B1 genes showed considerable higher sequence identities (97.2–98.4%) to those of group B rotaviruses detected in India (CAL‐1 in 1998) and Bangladesh (Bang373 and Bang544 in 2000 and 2001, respectively) than to those of Chinese strains (90.7–93.6%) (ADRV and WH‐1 in 1982 and 2002, respectively). Phylogenetically, the four genes of MMR‐B1 were clustered into the Indian–Bangladeshi lineage. Although the deduced amino acid sequences of MMR‐B1 were similar to those of strains CAL‐1 and Bang373, several amino acids in VP8* were found to be different from those of the group B rotaviruses described previously. The first detection in Myanmar of a human group B rotavirus suggested endemic distribution or expansion of the group B rotavirus of the Indian–Bangladeshi lineage in Southeast Asia. J. Med. Virol. 81:1968–1974, 2009. © 2009 Wiley‐Liss, Inc.     

Essential trauma management training: addressing service delivery needs in active conflict zones in eastern Myanmar

Introduction  

Access to governmental and international nongovernmental sources of health care within eastern Myanmar's conflict regions is virtually nonexistent. Historically, under these circumstances effective care for the victims of trauma, particularly landmine injuries, has been severely deficient. Recognizing this, community-based organizations (CBOs) providing health care in these regions sought to scale up the capacity of indigenous health workers to provide trauma care.     

Chemoprevention of familial adenomatous polyposis by natural dietary compounds sulforaphane and dibenzoylmethane alone and in combination in ApcMin/+ mouse

Cancer chemopreventive agent sulforaphane (SFN) and dibenzoylmethane (DBM) showed antitumorigenesis effects in several rodent carcinogenesis models. In this study, we investigated the cancer chemopreventive effects and the underlying molecular mechanisms of dietary administration of SFN and DBM alone or in combination in the ApcMin/+ mice model. Male ApcMin/+ mice (12 per group) at age of 5 weeks were given control AIN-76A diet, diets containing 600 ppm SFN and 1.0% DBM, or a combination of 300 ppm SFN and 0.5% DBM for 10 weeks. Mice were then sacrificed, and tumor numbers and size were examined. Microarray analysis, Western blotting, ELISA, and immunohistochemical staining were done to investigate the underlying molecular mechanisms of cancer chemopreventive effects of SFN and DBM. Dietary administrations of SFN and DBM alone or in combination significantly inhibited the development of intestinal adenomas by 48% (P=0.002), 50% (P=0.001), and 57% (P<0.001), respectively. Dietary administration of 600 ppm SFN and 1.0% DBM also reduced colon tumor numbers by 80% (P=0.016) and 60% (P=0.103), respectively, whereas the combination of SFN and DBM treatment blocked the colon tumor development (P=0.002). Both SFN and DBM treatments resulted in decreased levels of prostaglandin E2 or leukotriene B4 in intestinal polyps or apparently normal mucosa. Treatments also led to the inhibition of cell survival and growth-related signaling pathways (such as Akt and extracellular signal-regulated kinase) or biomarkers (such as cyclooxygenase-2, proliferating cell nuclear antigen, cleaved caspases, cyclin D1, and p21). In conclusion, our results showed that both SFN and DBM alone as well as their combination are potent natural dietary compounds for chemoprevention of gastrointestinal cancers.     

Decreasing Disparities in Breast Cancer Screening in Refugee Women Using Culturally Tailored Patient Navigation

BACKGROUND

Patient navigator (PN) programs can improve breast cancer screening in low income, ethnic/racial minorities. Refugee women have low breast cancer screening rates, but it has not been shown that PN is similarly effective.

OBJECTIVE

Evaluate whether a PN program for refugee women decreases disparities in breast cancer screening.

DESIGN

Retrospective program evaluation of an implemented intervention.

PARTICIPANTS

Women who self-identified as speaking Somali, Arabic, or Serbo-Croatian (Bosnian) and were eligible for breast cancer screening at an urban community health center (HC). Comparison groups were English-speaking and Spanish-speaking women eligible for breast cancer screening in the same HC.

INTERVENTION

Patient navigators educated women about breast cancer screening, explored barriers to screening, and tailored interventions individually to help complete screening.

MAIN MEASURES

Adjusted 2-year mammography rates from logistic regression models for each calendar year accounting for clustering by primary care physician. Rates in refugee women were compared to English-speaking and Spanish-speaking women in the year before implementation of the PN program and over its first 3 years.

RESULTS

There were 188 refugee (36 Somali, 48 Arabic, 104 Serbo-Croatian speaking), 2,072 English-speaking, and 2,014 Spanish-speaking women eligible for breast cancer screening over the 4-year study period. In the year prior to implementation of the program, adjusted mammography rates were lower among refugee women (64.1 %, 95 % CI: 49–77 %) compared to English-speaking (76.5 %, 95 % CI: 69 %–83 %) and Spanish-speaking (85.2 %, 95 % CI: 79 %–90 %) women. By the end of 2011, screening rates increased in refugee women (81.2 %, 95 % CI: 72 %–88 %), and were similar to the rates in English-speaking (80.0 %, 95 % CI: 73 %–86 %) and Spanish-speaking (87.6 %, 95 % CI: 82 %–91 %) women. PN increased screening rates in both younger and older refugee women.

CONCLUSION

Linguistically and culturally tailored PN decreased disparities over time in breast cancer screening among female refugees from Somalia, the Middle East and Bosnia.     

Autoimmune hepatitis: new paradigms in the pathogenesis,diagnosis, and management

Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver, and of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating γ-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4⁺ and CD8⁺ T cells are involved together with effector responses mediated by NK cells, γδ T cells, and macrophages. A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis.