No abstract

We propose that a cell's life is divided into two fundamentally different parts. Some time after mitosis all cells enter a state (A) in which their activity is not directed towards replication. A cell may remain in the A-state for any length of time, throughout which its probability of leaving A-state remains constant. On leaving A-state, cells enter B-phase in which their activities are deterministic, and directed towards replication. Initiation of cell replication processes is thus random, in the sense that radioactive decay is random. Cell population growth rates are determined by the probability with which cells leave the A-state, the duration of the B-phase, and the rate of cell death. Knowledge of these parameters permits precise calculation of the distribution of intermitotic times within populations, the behavior of synchronized cell cultures, and the shape of labeled mitosis curves.

Men seek help and use health services less frequently than women do. Men's help‐seeking practices and health service use are complex issues involving biological, psychological and sociological considerations. Most discussion on men's help‐seeking positions them as reluctant consumers or “behaving badly” with respect to their health. Few studies have explored whether health service providers are equipped to deal with men's health issues appropriately. The current health system appears not to be tailored to meet the health needs of men. Better collaboration is required across disciplines, to further investigate men's health using both qualitative and quantitative research methods.

Studies on why small and medium enterprises (SMEs) engage in proenvironmental behavior suggest that managers' environmental responsibility plays a relatively greater role than competitiveness and legitimacy-seeking. These categories of drivers are mostly considered independent of each other. Using survey data and comparative case studies of wine firms in South Africa, this study finds that managers' environmental responsibility is indeed the key driver in a context where state regulation hardly plays any role in regulating dispersed, rural firms. However, especially proactive firms are also characterized by expectations of competitiveness gains. The authors thus emphasize the role of institutional context and potential interaction effects between these drivers in explaining the reasons why SMEs engage in pro-environmental behavior in developing countries.

Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well‐characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth‐inhibitory effect. Their half‐maximal effective concentration (EC50) values were determined in chordoma cells and normal fibroblasts. Twenty‐seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho‐EGFR and its downstream pathways in a dose‐dependent manner. Analysis of substituent patterns suggested that EGFR‐inhibitors with small aniline substituents in the 4‐position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U‐CH1 xenograft and a patient‐derived xenograft, SF8894). One of the resistant cell lines (U‐CH2) was shown to express high levels of phospho‐MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p‐)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.