Summary Squamous cell carcinomas (SCCs) are heterogeneous tumors that are sustained by tumor propagating cancer cells (TPCs). SCCs frequently resist chemotherapy through mechanisms that are still unknown. Here, we combine H2BGFP based pulse-chasing with cell surface markers to distinguish quiescent from proliferative TPCs within SCCs. We find that quiescent TPCs resist DNA damage and exhibit increased tumorigenic potential in response to chemotherapy, whereas proliferative TPCs undergo apoptosis. Quiescence is regulated by TGFβ/SMAD signaling, which directly regulates cell cycle gene transcription to control a reversible G1 cell cycle arrest, independent of p21CIP function. Indeed, genetic or pharmacological TGFβ inhibition increases the susceptibility of TPCs to chemotherapy as it prevents entry into a quiescent state. These findings provide direct evidence that TPCs can reversibly enter a quiescent, chemoresistant state which underscores the need for combinatorial approaches to improve treatment of chemotherapy-resistant SCCs.

Although the principles that balance stem cell self-renewal and differentiation in normal tissue homeostasis are beginning to emerge, it is still unclear whether cancer cells with tumor initiating potential are similarly governed, or whether they have acquired distinct mechanisms to sustain self-renewal and long-term tumor growth. Here we show that the transcription factor Sox2, which is not expressed in normal skin epithelium and is dispensable for epidermal homeostasis, marks tumor initiating cells (TICs) in cutaneous squamous cell carcinomas (SCC). We demonstrate that Sox2 is required for SCC growth in mouse and human, where it enhances Nrp1/Vegf signaling to promote the expansion of TICs along the tumor-stroma interface. Our findings suggest that distinct transcriptional programs govern self-renewal and long-term growth of TICs and normal skin epithelial stem and progenitor cells. These programs present promising diagnostic markers and targets for cancer specific therapies.

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ABSTRACT. Joint management of protected areas is promoted in many countries around the world. It is considered a means to provide local communities, including indigenous people, with recognition of their cultural practices in the use and management of the natural resources within a protected area, while working together with governments to achieve conservation goals. However, implementation of effective joint management has often been difficult because capacities and expectations among partners differ. Here we explore the potential of using a participatory monitoring and evaluation approach as a means of not only agreeing among partners on the objectives of joint management but also of measuring progress toward those objectives. In particular, we first describe the process used to develop criteria and indicators for measuring joint management effectiveness of a protected area in the Northern Territory, Australia, involving the park's Aboriginal Traditional Owners, their legal representatives, government, and researchers. We then analyze the process of applying a participatory approach to developing indicators and its contribution to improving equity among the partners. We consider the effectiveness of a participatory process within the context of the relationships, capacities, skills, communication, and cross-cultural information sharing. We found that at the early stages of joint management, the partners mostly identify process indicators related to human and social capital assets. Cross-cultural engagement in the early stages of the monitoring and evaluation cycle is challenged by issues relating to communication, institutional and community capacities, representation, and flexibility in ways of working together while learning by doing. We conclude, however, that a participatory monitoring and evaluation approach in which partners agree equally on the identification of criteria and indicators to measure agreed management outcomes has the potential of improving equitable participation, decision making and working relationships, which in turn will lead to improved park management effectiveness and community outcomes.

In vitro-in vivo extrapolation of drug metabolism data obtained in enriched preparations of subcellular fractions rely on robust estimates of physiologically relevant scaling factors for the prediction of clearance in vivo. The purpose of the current study was to measure the microsomal and cytosolic protein per gram of kidney (MPPGK and CPPGK) in dog and human kidney cortex using appropriate protein recovery marker and evaluate functional activity of human cortex microsomes. Cytochrome P450 (CYP) content and glucose-6-phosphatase (G6Pase) activity were used as microsomal protein markers, whereas glutathione-S-transferase activity was a cytosolic marker. Functional activity of human microsomal samples was assessed by measuring mycophenolic acid glucuronidation. MPPGK was 33.9 and 44.0 mg/g in dog kidney cortex, and 41.1 and 63.6 mg/g in dog liver (n = 17), using P450 content and G6Pase activity, respectively. No trends were noted between kidney, liver, and intestinal scalars from the same animals. Species differences were evident, as human MPPGK and CPPGK were 26.2 and 53.3 mg/g in kidney cortex (n = 38), respectively. MPPGK was 2-fold greater than the commonly used in vitro-in vivo extrapolation scalar; this difference was attributed mainly to tissue source (mixed kidney regions versus cortex). Robust human MPPGK and CPPGK scalars were measured for the first time. The work emphasized the importance of regional differences (cortex versus whole kidney–specific MPPGK, tissue weight, and blood flow) and a need to account for these to improve assessment of renal metabolic clearance and its extrapolation to in vivo.

Elevated blood pressure may occur in some patients with cardiac tamponade who have preexisting hypertension. Moreover, blood pressure may fall after pericardiocentesis in patients who have elevated blood pressure associated with tamponade.