Context matters-consensus molecular subtypes of colorectal cancer as biomarkers for clinical trials.

The Colorectal Cancer Subtyping Consortium identified four gene expression consensus molecular subtypes, CMS1 (immune), CMS2 (canonical), CMS3 (metabolic), and CMS4 (mesenchymal), using multiple microarray or RNA-sequencing datasets of primary tumor samples mainly from early stage colon cancer patients. Consequently, rectal tumors and stage IV tumors (possibly reflective of more aggressive disease) were underrepresented, and no chemo- and/or radiotherapy pretreated samples or metastatic lesions were included. In view of their possible effect on gene expression and consequently subtype classification, sample source and treatments received by the patients before collection must be carefully considered when applying the classifier to new datasets. Recently, several correlative analyses of clinical trials demonstrated the applicability of this classification to the metastatic setting, confirmed the prognostic value of CMS subtypes after relapse and hinted at differential sensitivity to treatments. Here, we discuss why contexts and equivocal factors need to be taken into account when analyzing clinical trial data, including potential selection biases, type of platform, and type of algorithm used for subtype prediction. This perspective article facilitates both our clinical and research understanding of the application of this classifier to expedite subtype-based clinical trials.

45-year follow-up of hepatitis C virus infection in healthy young adults.

BACKGROUND: The sequelae during the first two decades after acute hepatitis C virus (HCV) infection have been well studied, but the outcome thereafter is unknown. OBJECTIVE: To conduct an extended study of the natural history of HCV infection by using archived serum specimens originally collected between 1948 and 1954. DESIGN: Retrospective cohort study. SETTING: A university, a Veterans Affairs medical center, and a medical follow-up agency that had access to the serum specimens and accompanying demographic and medical records. PARTICIPANTS: 8568 military recruits who were evaluated for group A streptococcal infection and acute rheumatic fever between 1948 and 1954. Blood samples were taken from the recruits and, after testing, were stored frozen for almost 45 years. MEASUREMENTS: The presence of antibodies to HCV was determined by enzyme-linked immunoassay, supplementary recombinant immunoblot assay, and polymerase chain reaction for HCV RNA. Morbidity and mortality were also assessed. RESULTS: Of 8568 persons, 17 (0.2%) had positive results on enzyme-linked immunosorbent assay and recombinant immunoblot assay. The rate was 1.8% among the African-American persons and 0.1% among the white persons in the total sample (relative risk, 25.9 [95% CI, 8.4 to 80.0]). During the 45-year follow-up, liver disease occurred in 2 of the 17 HCV-positive persons (11.8%) and 205 of the 8551 HCV-negative persons (2.4%) (ethnicity-adjusted relative risk, 3.56 [CI, 0.94 to 13.52]). Seven of the 17 HCV-positive persons (41 %) and 2226 of the 8551 HCV-negative persons (26%) had died by December 1996 (ethnicity-adjusted relative risk, 1.48 [CI, 0.8 to 2.6]). Of persons who were HCV-positive, 1 (5.9%) died of liver disease 42 years after the original phlebotomy, 5 (29%) died of non-liver-related disease a median of 37 years after the original phlebotomy, and 1 (5.9%) died of unknown causes. One hundred nineteen HCV-negative persons (1.4%) died of liver disease. CONCLUSIONS: The rate of HCV infection from 1948 to 1954 among a sample of military recruits parallels that among present-day military recruits and volunteer blood donors. During 45 years of follow-up, HCV-positive persons had low liver-related morbidity and mortality rates. This suggests that healthy HCV-positive persons may be at less risk for progressive liver disease than is currently thought.

Influence of sulfhydryl reagents on potassium-stimulated calcium uptake by rat brain synaptosomes.

Potassium-stimulated calcium uptake by rat brain synaptosomes was measured by placing synaptosomes in a high (70 mM) potassium medium containing 45Ca. K+-stimulated uptake was essentially complete within 20 s. K+-stimulated calcium uptake was inhibited by pretreating the synaptosomes with N-ethylmaleimide, a sulfhydryl alkylating reagent. Methylmercury chloride and mercuric chloride inhibited K+-stimulated calcium uptake in the same concentration ranges at which they formed complexes with surface sulfhydryl groups. Ethylmercury chloride was considerably less effective at inhibiting calcium uptake and reacting with sulfhydryl groups. The presence of essential sulfhydryl moieties in the structures subserving K+-stimulated calcium uptake by nerve terminals is suggested.

The manager as a computer user.

Many people who are not computer experts are now making direct use of computer systems in the everyday performance of their duties. The manager is an example of a 'naive' computer user and he is currently the target of many systems which seek to improve his decision making performance by the provision of better and more up-to-date information. A questionnaire survey has been made of many different types of 'naive' computer user and this paper reports the results of interviews with managers who are computer users. Managers were questioned on the form of man-computer interaction they employed, the benefits they derived and the problems they encountered. The forms of interaction range from the regular receipt of standard printouts to the use of a teletype or visual display unit for data interrogation or to simulate the consequences of possible decisions. The results show that the standard outputs often make little contribution to the manager's work because they cannot respond to changes in the manager's information needs. The more complex forms of interaction are more flexible and can make a much greater contribution. However, the complexity of the interaction can be a major obstacle to effective use of the system by a busy manager and advanced systems are often under utilised.