K-Ras proteins are major drivers of human cancers, playing a direct causal role in about one million cancer cases/year. In cancers driven by mutant K-Ras, the protein is locked in the active, GTP-bound state constitutively, through a defect in the off-switch mechanism. As such, the mutant protein resembles the normal K-Ras protein from a structural perspective, making therapeutic attack extremely challenging. K-Ras is a member of a large family of related proteins, which share very similar GDP/GTP-binding domains, making specific therapies more difficult. Furthermore, Ras proteins lack pockets to which small molecules can bind with high affinity, with a few interesting exceptions. However, new insights into the structure and function of K-Ras proteins reveal opportunities for intervention that were not appreciated many years ago, when efforts were launched to develop K-Ras therapies. Furthermore, K-Ras undergoes post-translational modification and interactions with cellular signaling proteins that present additional therapeutic opportunities, such as specific binding to calmodulin and regulation of non-canonical Wnt signaling.

Ernst Lubitsch epitomized the transnationalism of the cinema in the 1920s as the first German director to come to Hollywood and one who brought over a number of German film artists to Hollywood over the course of the decade. In America he followed developments in German cinema in terms of technical innovations and popular genres, and he published in the German film press. The Student Prince in Old Heidelberg was meant to compete with similar silent operetta films being made in Germany, and making the film, Lubitsch had the chance to return to Germany for the first time since 1922. The film was transnational not only because of its connection to the movements of artists, technicians, ideas, styles, and genres back and forth across the Atlantic, but also for the ethnic, gender, and sexual politics of the film and its production itself: e.g., the “migration background” not just of Lubitsch but also of the film’s male star, Ramón Novarro.

Therapies for KRas cancers remain a major clinical need. In the current issue of Cancer Cell, Sanclemente and coworkers in Mariano Barbacid's group validate c-Raf as a prime target for these cancers. c-Raf ablation caused regression of advanced KRas^G12V/Trp53 tumors, without obvious systemic toxicity and without affecting MAPK signaling.

Drugs that target KRAS 12C covalently, AMG 510 and MRTX849, are now in the clinic. Recent papers describe development of these compounds, their selectivity and properties, early clinical data, and potential combination therapies. These papers herald a new era in Ras research, with improved drugs and strategies certain to follow.

A 58-year-old male patient presented to the emergency department with complaints of severe neck pain. He admitted to drug use but denied using intravenous (IV) drugs. On exam, he had a fever of 100.7 F, positive Kernig’s sign, and normal neurologic exam. The patient was suspected to have bacterial meningitis and was started on IV antibiotics. The next day the patient developed decreased hand grip. Magnetic resonance imaging of the spine the next day showed a soft-tissue mass impinging on the spinal canal. The patient was subsequently taken to the operating room where the epidural abscess was drained. [West J Emerg Med. 2012;13(6):505–506.]

KRAS proteins play a major role in human cancer, but have not yielded to therapeutic attack. New technologies in drug discovery and insights into signaling pathways that KRAS controls have promoted renewed efforts to develop therapies through direct targeting of KRAS itself, new ways of blocking KRAS processing, or by identifying targets that KRAS cancers depend on for survival. Although drugs that block the well-established downstream pathways, RAF-MAPK and PI3K, are being tested in the clinic, new efforts are under way to exploit previously unrecognized vulnerabilities, such as altered metabolic networks, or novel pathways identified through synthetic lethal screens. Furthermore, new ways of suppressing KRAS gene expression and of harnessing the immune system offer further hope that new ways of treating KRAS are finally coming into view. These issues are discussed in this edition of CCR Focus.

How the brain takes in information, makes a decision, and acts on this decision is strongly influenced by the ongoing and constant fluctuations of state. Understanding the nature of these brain states and how they are controlled is critical to making sense of how the nervous system operates, both normally and abnormally. While broadly projecting neuromodulatory systems acting through metabotropic pathways have long been appreciated to be critical for determining brain state, more recent investigations have revealed a prominent role for fast acting neurotransmitter pathways for temporally and spatially precise control of neural processing. Corticocortical and thalamocortical glutamatergic projections can rapidly and precisely control brain state by changing both the nature of ongoing activity and by controlling the gain and precision of neural responses.