The results showed that A. muricata was a promising new antioxidant and anticancer agent.

Growth-related oncogene (GRO), a member of the CXC chemokine subfamily, plays a major role in inflammation and wound healing. CXC chemokines have been found to be associated with tumorigenesis, angiogenesis, and metastasis. Although elevated expression of GRO has been reported in several human cancers, the expression and role of GRO and its receptor, CXCR2, in esophageal cancer are poorly understood. This study used real-time reverse transcription-PCR (RT-PCR) and immunohistochemical approaches to show that GROA, GROB, and CXCR2 are up-regulated in esophageal tumor tissue. Furthermore, GROA, GROB, and CXCR2 are constitutively expressed in WHCO1, an esophageal cancer cell line that was used as a model system here. GROB enhances transcription of EGR-1, via the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, which can be blocked by a specific antagonist of CXCR2 (SB 225002) or specific antibody to GROB. WHCO1 cells treated with SB 225002 exhibited a 40% reduction in cell proliferation. A stable WHCO1 GROA RNA interference (RNAi) clone displayed a 43% reduction in GROA mRNA levels as determined by real-time RT-PCR, reduced levels of GROA by fluorescence microscopy, and a 60% reduction in the levels of phosphorylated ERK1/2. A stable clone expressing GROB RNAi displayed >95% reduction in GROB mRNA levels, reduced levels of GROB by fluorescence microscopy, and an 80% reduction in the levels of phosphorylated ERK1/2. Moreover, these GROA RNAi-and GROB RNAiexpressing clones displayed a 20% and 50% decrease in cell proliferation, respectively. Our results suggest that GROA-CXCR2 and GROB-CXCR2 signaling contributes significantly to esophageal cancer cell proliferation and that this autocrine signaling pathway may be involved in esophageal tumorigenesis. (Cancer Res 2006; 66(6): 3071-7)

Annona muricata (A. muricata) is a tropical plant species belonging to family Annonaceae and known for its many medicinal uses. This review focuses on the research history of its traditional uses, phytochemicals, pharmacological activities, toxicological aspects of the extracts and isolated compounds, as well as the in vitro propagation studies with the objective of stimulating further studies on this plant for human consumption and treatment. A. muricata extracts have been identified in tropical regions to traditionally treat diverse conditions ranging from fever to diabetes and cancer. More than 200 chemical compounds have been identified and isolated from this plant, the most important being alkaloids, phenols and acetogenins. Using in vitro studies, its extracts and phytochemicals have been characterized as antioxidant, anti-microbial, anti-inflammatory, insecticidal, larvicidal, and cytotoxic to cancer cells. In vivo studies have revealed anxiolytic, anti-stress, anti-inflammatory, immunomodulatory, antimalarial, antidepressant, gastro protective, wound healing, hepato-protective, hypoglycemic, anticancer and anti-tumoral activities. In silico studies have also been reported. In addition, clinical studies support the hypoglycemic as well as some anticancer activities. Mechanisms of action of some pharmacological activities have been elucidated. However, some phytochemical compounds isolated from A. muricata have shown a neurotoxic effect in vitro and in vivo, and therefore, these crude extracts and isolated compounds need to be further investigated to define the magnitude of the effects, optimal dosage, and mechanisms of action, long-term safety, and potential side effects. Additionally, more clinical studies are necessary to support the therapeutic potential of this plant. Some studies were also found to have successfully regenerated the plant in vitro, but with limited success. The reported toxicity notwithstanding, A. muricata extracts seem to be some of the safest and promising therapeutic agents of the 21st century and beyond that need to be studied further for better medicinal formulations and diseases management.

Purpose: To elucidate the molecular mechanisms contributing to the unique clinicopathologic characteristics of mucinous ovarian carcinoma, global gene expression profiling of mucinous ovarian tumors was carried out. Experimental Design: Gene expression profiling was completed for 25 microdissected mucinous tumors [6 cystadenomas, 10 low malignant potential (LMP) tumors, and 9 adenocarcinomas] using Affymetrix U133 Plus 2.0 oligonucleotide microarrays. Hierarchical clustering and binary tree prediction analysis were used to determine the relationships among mucinous specimens and a series of previously profiled microdissected serous tumors and normal ovarian surface epithelium. PathwayAssist software was used to identify putative signaling pathways involved in the development of mucinous LMP tumors and adenocarcinomas. Results: Comparison of the gene profiles between mucinous tumors and normal ovarian epithelial cells identified 1,599, 2,916, and 1,765 differentially expressed in genes in the cystadenomas, LMP tumors, and adenocarcinomas, respectively. Hierarchical clustering showed that mucinous and serous LMP tumors are distinct. In addition, there was a close association of mucinous LMP tumors and adenocarcinomas with serous adenocarcinomas. Binary tree prediction revealed increased heterogeneity among mucinous tumors compared with their serous counterparts. Furthermore, the cystadenomas coexpressed a subset of genes that were differentially regulated in LMP and adenocarcinoma specimens compared with normal ovarian surface epithelium. PathwayAssist highlighted pathways with expression of genes involved in drug resistance in both LMP and adenocarcinoma samples. In addition, genes involved in cytoskeletal regulation were specifically up-regulated in the mucinous adenocarcinomas. Conclusions:These data provide a useful basis for understanding the molecular events leading to the development and progression of mucinous ovarian cancer.Epithelial ovarian cancer is the fourth leading cause of cancer deaths in women in the United States (1). An estimated 22,220 new cases of this malignancy will be diagnosed, and f16,210 deaths attributed to this disease in the United States during 2005 (1). This high case fatality rate is due in part to the fact that the majority of patients (75%) are diagnosed after extraovarian spread of the disease has occurred. The 5-year survival rate for women with the late-stage disease is 25% compared with a rate of >90% for women with early-stage (2, 3).The histologic classification of ovarian carcinomas is based on morphologic criteria and corresponds to the different types of epithelia in the female reproductive system, including papillary serous, mucinous, endometrioid, clear cell, and Brenner (transitional; ref. 4). Each class has been further subclassified into benign, malignant, and borderline or low malignant potential (LMP) to reflect their histopathology. Mucinous ovarian tumors account for 12% to 15% of all ovarian neoplasms. The majority of mucinous ovarian tumors are beni...

Multiplicity of infection (MOI) and genetic diversity of P. falciparum infections are important surrogate indicators for assessing malaria transmission intensity in different regions of endemicity. Determination of MOI and diversity of P. falciparum among asymptomatic carriers will enhance our understanding of parasite biology and transmission to mosquito vectors. This study examined the MOI and genetic diversity of P. falciparum parasite populations circulating in Mbita, a region characterized as one of the malaria hotspots in Kenya. The genetic diversity and multiplicity of P. falciparum infections in 95 asymptomatic school children (age 5–15 yrs.) residing in Mbita, western Kenya were assessed using 10 polymorphic microsatellite markers. An average of 79.69% (Range: 54.84–95.74%) of the isolates analysed in this study were polyclonal infections as detected in at least one locus. A high mean MOI of 3.39 (Range: 2.24–4.72) and expected heterozygosity (He) of 0.81 (Range: 0.57–0.95) was reported in the study population. The analysed samples were extensively polyclonal infections leading to circulation of highly genetically diverse parasite populations in the study area. These findings correlated with the expectations of high malaria transmission intensity despite scaling up malaria interventions in the area thereby indicating the need for a robust malaria interventions particularly against asymptomatic carriers in order to attain elimination in the region.

BackgroundThe Quinine tree (Rauvolfia caffra) is used as a medicinal plant among traditional communities in many countries to manage tumors and other diseases associated with oxidative stress. To validate indigenous knowledge and possibly position this herb for technology uptake and utilization, we established the level of antioxidant activity in R. caffra, and probed for the presence of associated phytochemicals.MethodsAntioxidant activity was determined on 1,1-diphenyl-2-picrylhydrazyl (DPPH) while major phytochemicals were identified by multiple tests on methanol fractions.ResultsR. caffra showed promise as a cure, with antioxidant activity comparable to the commercially used drug quercetin (R. caffra = 79.7% ±1.9; quercetin = 82.6% ± 2.0). However, we found two phytochemicals with possible antagonistic effect: co-occurrence of alkaloids and saponins significantly reduced antioxidant activity (alkaloids only = 63%; alkaloids plus saponins = 15%; steroids, terpenoids and cardiac glycosides = 82%), thus alkaloids and saponins should be exclusive to each other in drug formulations.ConclusionsAntagonistic relationship among phytochemicals would affect the efficacy of crude extracts as used in traditional medicine. Unlike in herbal medicine, use of modern biotechnology in extraction, purification and design of optimal combinations will ensure efficient drug formulations with optimum bioactivity and minimum toxicity. Metabolic pathway engineering under a controlled environment may optimize availability of desired compounds.

Reports of increasing worldwide circulation of human enterovirus-68 (EV68) are well documented. Despite health concerns posed by resurgence of these viruses, little is known about EV68 strains circulating in Kenya. In this study, we characterized 13 EV68 strains isolated in Kenya between 2008 and 2011 based on the Hypervariable 3′- end of the VP1 gene. Viral RNA was extracted from the isolates and partial VP1 gene amplified by RT-PCR, followed by nucleotide sequencing. Alignment of deduced amino acid sequences revealed substitutions in Kenyan EV68 isolates absent in the prototype reference strain (Fermon). The majority of these changes were present in the BC and DE-loop regions, which are associated with viral antigenicity and virulence. The Kenyan strains exhibited high sequence homology with respect to those from other countries. Natural selection analysis based on the VP1 region showed that the Kenyan EV68 isolates were under purifying selection. Phylogenetic analysis revealed that majority (84.6%) of the Kenyan strains belonged to clade A, while a minority belonged to clades B and C. Overall, our results illustrate that although EV68 strains isolated in Kenya were genetically and antigenically divergent from the prototype strain (Fermon), they were closely related to those circulating in other countries, suggesting worldwide transmissibility. Further, the presence of shared mutations by Kenyan EV68 strains and those isolated in other countries, indicates evolution in the VP1 region may be contributing to increased worldwide detection of the viruses. This is the first study to document circulation of EV68 in Kenya.

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