Heparin, the most widely used anticoagulant drug in the world today, remains an animal-derived product with the attendant risks of adulteration and contamination. A contamination crisis in 2007–2008 increased the impetus to provide non-animal-derived sources of heparin, produced under cGMP conditions. In addition, recent studies suggest that heparin may have significant antineoplastic activity, separate and distinct from its anticoagulant activity, while other studies indicate a role for heparin in treating inflammation, infertility, and infectious disease. A variety of strategies have been proposed to produce a bioengineered heparin. In this review, we discuss several of these strategies including microbial production, mammalian cell production, and chemoenzymatic modification. We also propose strategies for creating “designer” heparins and heparan-sulfates with various biochemical and physiological properties.

The ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet that leads to nutritional ketosis and weight loss. It is known to induce ketosis but is not an established cause of clinically significant ketoacidosis. Lactation ketoacidosis is well established in bovine literature but remains a rare phenomenon in humans. Here we present a life-threatening case of severe ketoacidosis in a nondiabetic lactating mother on a strict ketogenic diet. We review the available case reports of lactation ketoacidosis in humans and the mechanisms thereof. Although ketogenic diet has been shown to be safe in nonpregnant individuals, the safety of this diet in lactating mothers is not known. Health professionals and mothers should be made aware of the potential risk associated with a strict ketogenic diet when combined with lactation. Prompt diagnosis and immediate treatment cannot be overemphasized. To our knowledge, this is the first reported case of life-threatening lactation ketoacidosis associated with ketogenic diet while consuming an adequate number of calories per day.

Non–small cell lung cancer (NSCLC) cells with oncogenic mutant p53 (Onc-p53) alleles exhibit significantly higher levels of proteasome activity, indicating that Onc-p53 induces proteotoxic stress which may be leveraged as a therapeutic vulnerability. Proteasome inhibitors (PI) are most active in cells under proteotoxic stress, so we investigated whether PIs exhibit preferential cytotoxicity in Onc-p53 NSCLC cells. Indeed, bortezomib (BTZ) and other PIs exhibited IC50 values 6- to 15-fold lower in Onc-p53 cells versus wild-type (WT) p53 cells. BTZ cytotoxic effects in Onc-p53 cells were abrogated by antioxidants such as N-acetyl-L-cysteine, indicating that oxidative stress is the critical driver of BTZ-dependent cytotoxic effects in Onc-p53 cells. Importantly, we observed oxidative stress–dependent transcriptional induction of the proapoptotic BH3-only protein NOXA, leading to cleavage of caspase-3, consistent with an apoptotic mechanism of cell death in Onc-p53 but not in WT p53 cells treated with BTZ. BTZ-generated oxidative stress was linked to nuclear translocation of NRF2 and transcriptional activation of ATF3, which in turn was required for NOXA induction. Validating the translational potential of BTZ in Onc-p53 NSCLC cells, BTZ and the BH3-mimetic navitoclax were synergistically cytotoxic in Onc-p53 but not in WTp53 cells in vitro, and BTZ effectively limited the growth of Onc-p53 NSCLC xenografts when combined with navitoclax and carboplatin (a standard-of-care chemotherapeutic in NSCLC) in vivo. Our data therefore support further investigation of the therapeutic utility of PIs combined with BH3-mimetics and chemotherapy in Onc-p53 human NSCLC as a novel therapeutic strategy. Significance: NSCLC is the leading cause of cancer death due, in part, to a lack of active therapies in advanced disease. We demonstrate that combination therapy with a proteasome inhibitor, BH3-mimetic, and chemotherapy is an active precision therapy in NSCLC cells and tumors expressing Onc-p53 alleles.

Historically, systemic therapy for resectable non-small cell lung cancer (NSCLC) has been associated with a modest impact on overall survival. The current treatment options for early-stage resectable NSCLC include neoadjuvant, adjuvant, and perioperative immunotherapy in combination with chemotherapy. In this review, we explore the current treatment paradigms and emerging opportunities for improved survival outcomes from using immunotherapeutic approaches in the treatment of early-stage resectable NSCLC. The incorporation of immunotherapy into neoadjuvant, adjuvant, and perioperative treatment of surgically resectable NSCLC has yielded improved outcomes beyond chemotherapy-alone approaches. Despite this, there remains a margin for improving survival outcomes for patients. Clinical trials utilizing novel agents and approaches that modulate the anti-tumor immune response are currently ongoing and will likely inform the future treatment landscape for early-stage surgically resectable NSCLC.

The current standard of care for inoperable stage III non-small cell lung cancer (NSCLC) is concurrent chemotherapy and radiation therapy with consolidation durvalumab. Despite this approach, about 50% of patients will experience disease recurrence, with about half of recurrence events occurring at distant metastatic sites. In this review, the authors performed a structured analysis of the available clinical trial data and literature related to the treatment of this disease. The authors discuss the detriments and merits of several of these trials and explore clinical and preclinical data that contribute to the growing body of literature supporting a future with new approaches, including new techniques in radiation therapy, sequencing, and agents. Upcoming trials may illuminate a path towards better outcomes for patients in this setting.