Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids. We also showed that the increase in ceramide levels contributes to some extent in the mediation of apoptosis. Consistent with this mechanism of action, Fasnall showed potent anti-tumor activity in the MMTV-Neu model of HER2(+) breast cancer, particularly when combined with carboplatin.

Summary Inducible Hsp70 (Hsp70i) is overexpressed in a wide spectrum of human tumors and its expression correlates with metastasis, poor outcomes, and resistance to chemotherapy in patients. Identification of small molecule inhibitors selective for Hsp70i could provide new therapeutic tools for cancer treatment. In this work, we used fluorescence-linked enzyme chemoproteomic strategy (FLECS) to identify HS-72, an allosteric inhibitor selective for Hsp70i. HS-72 displays the hallmarks of Hsp70 inhibition in cells, promoting substrate protein degradation and growth inhibition. Importantly, HS-72 is selective for Hsp70i over the closely related constitutively active Hsc70. Studies with purified protein show HS-72 acts as an allosteric inhibitor, reducing ATP affinity. In vivo HS-72 is well-tolerated, showing bioavailability and efficacy, inhibiting tumor growth and promoting survival in a HER2+ model of breast cancer. The HS-72 scaffold is amenable to resynthesis and iteration, suggesting an ideal starting point for a new generation of anticancer therapeutics targeting Hsp70i.

No abstract

Bochdalek hernia is a congenital diaphragmatic hernia that presents rarely in adulthood. Because of the paucity of cases, no standard repair technique has been identified. Here we present two cases of robotic, thoracoscopic repair of this rare hernia defect. Two separate adult patients with right-sided abdominal pain presented to the emergency department for evaluation. Both patients were diagnosed with right-sided Bochdalek hernia and repair was undertaken with a robotic, transthoracic approach. Repair technique is described in detail, including port placement, dissection technique, and repair strategy. Advantages of the robotic, transthoracic approach are discussed in detail. A transthoracic minimally invasive approach using a robotic platform is noted to be both feasible and practical in the treatment of adult Bochdalek hernia.

Storytelling teaches. All good storytelling is good teaching. Storytelling is a form of teaching and learning because it asks the readers or listeners to replace well-established explanations that are considered facts with new, unexpected ones. We always learn new things when listening to good stories. Good stories do so by violating expectations and surprising the listener or the reader. Surprise breeds suspense, which generates engagement, which is a catalyst for learning -even truer for scientific and data-driven stories. In this paper we show how understanding the nature of good stories by focusing on the novelty they introduce and assumption they violate helps us to do effective scientific work and tell excellent data-based stories. We start by providing definitions of "story, " "storytelling, " and "good stories. " We then outline a methodology for building stories and provide an illustrative example of an effective data-based story from the history of medicine.