In vitro hypoxia-conditioned colon cancer cell lines derived from HCT116 and HT29 exhibit altered apoptosis susceptibility and a more angiogenic profile in vivo

Hypoxia is an important selective force in the clonal evolution of tumours. Through HIF-1 and other transcription factors combined with tumour-specific genetic alterations, hypoxia is a dominant factor in the angiogenic phenotype. Cellular adaptation to hypoxia is an important requirement of tumour progression independent of angiogenesis. The adaptive changes, insofar as they alter hypoxia-induced apoptosis, are likely to determine responsiveness to antiangiogenic strategies. To investigate this adaptation of tumour cells to hypoxia, we recreated in vitro the in vivo situation of chronic intermittent exposure to low-oxygen levels. The colon carcinoma cell lines HT29 and HCT116 were subjected to 40 episodes of sublethal hypoxia (4 h) three times a week. The resulting two hypoxia-conditioned cell lines have been maintained in culture for more than 2 years. In both cell lines changes in doubling times occurred: in HT29 an increase, and in HCT116 a decrease. Cell survival in response to hypoxia and to DNA damage differed strikingly in the two cell lines. The HT29 hypoxia-conditioned cells were more resistant than the parental line to a 24 h hypoxic challenge, while those from HCT116 surprisingly were more sensitive. Sensitivity to cisplatin in vitro was also significantly different for the hypoxia-conditioned compared with the parental lines, suggesting a change in pathways leading to apoptosis following DNA damage signaling. The growth of both conditioned cell lines in vivo as xenografts in immunodeficient (SCID) mice was more rapid than their parental lines, and was accompanied in each by evidence of enhanced vascular proliferation as a consequence of the hypoxia-conditioning. Thus the changes in apoptotic susceptibility were independent of altered angiogenesis. The derivation of these lines provides a model for events within hypoxic regions of colon cancers, and for the acquisition of resistance and sensitivity characteristics that may have therapeutic implications for the use of antiangiogenesis drugs

A cost-effectiveness analysis evaluating endoscopic surveillance for gastric cancer for populations with low to intermediate risk

10.1371/journal.pone.0083959PLoS ONE812-POLN

Human malarial disease: a consequence of inflammatory cytokine release

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease

Evidence for cervical cancer mortality with screening program in Taiwan, 1981–2010: age-period-cohort model

<p>Abstract</p> <p>Background</p> <p>Cervical cancer is the most common cancer experienced by women worldwide; however, screening techniques are very effective for reducing the risk of death. The national cervical cancer screening program was implemented in Taiwan in 1995. The objective of this study was to examine and provide evidence of the cervical cancer mortality trends for the periods before and after the screening program was implemented.</p> <p>Methods</p> <p>Data from 1981 to 2010 of the causes of death registered were obtained from the Department of Health, Taiwan. Age-standardized mortality rates, age-specific rates, and age-period-cohort models that employed the sequential method were used to assess temporal changes that occurred between 1981 and 2010, with 1995 used as the separating year.</p> <p>Results</p> <p>The results showed that for both time periods of 1981 to 1995 and 1996 to 2010, age and period had significant effects, whereas the birth cohort effects were insignificant. For patients between 80 and 84 years of age, the mortality rate for 1981 to 1995 and 1996 to 2010 was 48.34 and 68.08. The cervical cancer mortality rate for 1996 to 2010 was 1.0 for patients between 75 and 79 years of age and 1.4 for patients between 80 and 84 years of age compared to that for 1981 to 1995. Regarding the period effect, the mortality trend decreased 2-fold from 1996 to 2010.</p> <p>Conclusions</p> <p>The results of this study indicate a decline in cervical cancer mortality trends after the screening program involving Papanicolaou tests was implemented in 1995. However, the positive effects of the screening program were not observed in elderly women because of treatment delays during the initial implementation of the screening program.</p

Quality of Online Pharmacies and Websites Selling Prescription Drugs: A Systematic Review

Background: Online pharmacies are companies that sell pharmaceutical preparations, including prescription-only drugs, on the Internet. Very little is known about this phenomenon because many online pharmacies operate from remote countries, where legal bases and business practices are largely inaccessible to international research. Objective: The aim of the study was to perform an up-to-date and comprehensive review of the scientific literature focusing on the broader picture of online pharmacies by scanning several scientific and institutional databases, with no publication time limits. Methods: We searched 4 electronic databases up to January 2011 and the gray literature on the Internet using the Google search engine and its tool Google Scholar. We also investigated the official websites of institutional agencies (World Health Organization, and US and European centers for disease control and drug regulation authorities). We focused specifically on online pharmacies offering prescription-only drugs. We decided to analyze and report only articles with original data, in order to review all the available data regarding online pharmacies and their usage. Results: We selected 193 relevant articles: 76 articles with original data, and 117 articles without original data (editorials, regulation articles, or the like) including 5 reviews. The articles with original data cover samples of online pharmacies in 47 cases, online drug purchases in 13, consumer characteristics in 15, and case reports on adverse effects of online drugs in 12. The studies show that random samples with no specific limits to prescription requirements found that at least some websites sold drugs without a prescription and that an online questionnaire was a frequent tool to replace prescription. Data about geographical characteristics show that this information can be concealed in many websites. The analysis of drug offer showed that online a consumer can get virtually everything. Regarding quality of drugs, researchers very often found inappropriate packaging and labeling, whereas the chemical composition usually was not as expected in a minority of the studies’ samples. Regarding consumers, the majority of studies found that not more than 6% of the samples had bought drugs online. Conclusions: Online pharmacies are an important phenomenon that is continuing to spread, despite partial regulation, due to intrinsic difficulties linked to the impalpable and evanescent nature of the Web and its global dimension. To enhance the benefits and minimize the risks of online pharmacies, a 2-level approach could be adopted. The first level should focus on policy, with laws regulating the phenomenon at an international level. The second level needs to focus on the individual. This approach should aim to increase health literacy, required for making appropriate health choices, recognizing risks and making the most of the multitude of opportunities offered by the world of medicine 2.0

The role of change management in implementing the offshore outsourcing business model: a processual view

Organizational change, Offshore IT outsourcing, Case study,