Canadian Cancer Trials Group (CCTG) IND215: A phase Ib study of Selumetinib in patients with untreated advanced or metastatic NSCLC who are receiving standard chemotherapy regimens.

Introduction Selumetinib (AZD6244, ARRY-142886) is a potent inhibitor of MEK1/2, thereby inhibiting phosphorylation of ERK2. We investigated the toxicity and the recommended phase II dose of the combination of selumetinib with two platinum based first line chemotherapy combinations in non-small cell lung cancer. Methods This was a phase I trial of escalating doses of selumetinib with carboplatin (AUC 6), paclitaxel (200 mg/m2) (cohort 1) or pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) (cohort 2) in patients with chemotherapy naïve, advanced or metastatic NSCLC. Patients enrolled on cohort 2 had non-squamous histology. Dose escalation of selumetinib proceeded using a 3 + 3 design: 50 mg b.i.d. days 2-19 (dose level 1); 75 mg b.i.d. days 2-19 (dose level 2); and 75 mg b.i.d. continuously. Adverse events were evaluated using CTC AE v4 and response by RECIST 1.1. Results Thirty-nine patients were enrolled (cohort 1 n = 16; cohort 2, n = 23). There were no dose limiting toxicities in either cohort and the recommended phase II dose for both regimens was standard doses of carboplatin, paclitaxel or pemetrexed and cisplatin with continuous selumetinib at a dose of 75 mg b.i.d. Most adverse events were grade 1 or 2 and were predominantly diarrhea, nausea, stomatitis, peripheral edema, neutropenia, and skin rash. Response rate was 37.5% for cohort 1 and 30.4% for cohort 2. Conclusion Selumetinib at a dose of 75 mg b.i.d continuously can be safely combined with paclitaxel and carboplatin or pemetrexed and cisplatin in patients with advanced or metastatic NSCLC. This trial provided the dose for the regimens used in a randomized phase II trial in NSCLC (CCTG IND.219).

Development of a graphical resilience framework to understand a coupled human-natural system in a remote arid highland of Baja California Sur.

Hydrological systems are important to society as water resources and effective management requires an understanding of how water and humans influence each other. To describe human-water connections it is necessary to bridge social and natural sciences. To this end, we construct an interdisciplinary graphical framework for evaluating potential human-water system resilience, which is a tool to show the spatial and temporal response to system change of both human and natural systems. This helps to identify the ways that human responses to change relate to changing water resources and identifies important thresholds and potential disconnects that would create vulnerability. We further use this tool to describe a dynamic, coupled human-water system present in the arid Sierra de la Giganta region of Baja California Sur, Mexico. In this remote mountain range, there is a community (self-identifying as Choyeros) who rely on spring water for ranching and subsistence. Using mixed methods of hydrogeochemistry and anthropology, we describe spatial connectivity and temporal changes of both hydrologic and social systems. We use these observations to examine the Choyero response to system changes and explore the topology of the various approaches that the community employs to adapt to changing water availability. The framework guides dialogue to constrain the types of policies, strategies, and responses that help to promote the sustainability of water resources. This framework can be used to compare systems across spatio-temporal scales to produce more generalizable and communicable insights of coupled human-natural systems. Supplementary Information: The online version contains supplementary material available at 10.1007/s11625-022-01101-6.

Ribonucleotide diphosphate reductase from human metastatic melanoma.

Cell free extracts from metastases of human melanoma contain a highly active ribonucleoside diphosphate reductase (RR) which uses guanosine diphosphate (GDP) as substrate and deoxythymidine triphosphate (dTTP) as effector. No activity could be detected in these extracts when cytidine diphosphate (CDP) was used as the substrate with adenosine triphosphate (ATP) as effector. The activity of this RR required the presence of either magnesium or calcium: there was a time lag before cell extracts from melanotic melanoma metastases showed full activities, but extracts from amelanotic tumors showed normal kinetics in the presence of these divalent cations. By contrast to other RRs, the activities in cell-free extracts could not be inhibited by hydroxyurea (10(-2) M). Even though an activity related free radical could be detected by electron paramagnetic resonance spectroscopy at 77 degrees K, the signal could not be quenched by 10(-2) M of this free radical trap. However, after ammonium sulphate fractionation, enzyme activity from melanotic melanoma was inhibited by 66% in 1 h. In the presence of substrates, effector and cofactors, the radical signal at g = 2.009 was also quenched by 60%; in the absence of substrate, effectors and cofactors, this signal was unaffected. These results indicate that two different free radicals must be present on melanoma RR. One is present in the resting enzyme, and the other is used during catalytic activity. The thiolate-active site of RR from melanoma was inhibited by the new nitrosourea anti-tumour drug fotemustine (IC50 = 10(-4) M as determined from a dose-response study).(ABSTRACT TRUNCATED AT 250 WORDS)

Perforation of the postpartum uterus with an intrauterine contraceptive device.

PIP: A case of perforation of the uterus at the time of insertion of the Birnberg bow IUD in a lactating, amenorrheic woman is presented. The patient, a 25-year-old gravida 2, had the IUD inserted 2 months after delivery. Perforation occurred at the time of insertion, causing a 2 mm puncture wound in the fundus. It appeared that the perforation was caused by the expulsion of the bow from the introducer, not by uterine dilation. Although the patient's uterus appeared grossly normal and well involuted, it was extremely soft. This case raises questions about the timing of the insertion of an IUD in a lactating, amenorrheic woman. It has been commonly assumed that involution requires about 6 weeks and that lactation speeds this process. However, it is recommended that this assumption be reassessed and that insertion of any IUD be delayed until regular menses have been re-established.^ieng