Explore the vast range of titles available.

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 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.

PurposeA recently published phase 2 neoadjuvant trial in patients with early-stage non-small cell lung cancer (NSCLC) (NCT02818920) evaluated the potential efficacy of pembrolizumab administration in the absence of chemotherapy. This communication reports on conventional and distribution-based immune profiling efforts in efforts to identify novel biomarkers predictive of benefit.MethodsPatients with stage 1B-3A NSCLC received two cycles of pembrolizumab (P), followed by surgical resection of the remaining tumors (NCT02818920). Banked peripheral blood mononuclear cells (PBMCs) were analyzed at baseline and following the second dose of P. Resected tumors were disaggregated, and cells were viably cryopreserved. Based on pathologic examination of the tumors, patients were categorized as major pathologic responders (MPR; ≤10% viable tumor present), or non-MPR (>10% viable tumor present). High-parameter immune phenotyping by flow cytometry was performed on all available tumor and PBMC specimens, and results were expressed using both conventional phenotypic frequency analyses as well as a novel distribution-based biomarker identification strategy aimed at discovery of patterns associated with MPR.ResultsConventional, frequency-based flow cytometric immune phenotyping of participant tumor microenvironments and PBMC revealed several MPR-associated trends, only a few of which reached statistical significance. The distribution-based biomarker identification strategy greatly enhanced the discovery of statistically significant cell types and patterns of change associated with MPR.ConclusionsThis novel, distribution-based analytic framework identified MPR-associated immune cell subsets in baseline PBMC that were not evident using conventional frequency-based immune profiling. Profiling the microenvironment of MPR-associated tumors revealed statistically significant distributional differences among highly expressed cellular markers on CD8+ cells.

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.

BackgroundOur study was designed to determine the safety, efficacy, and immunological effects of perioperative pembrolizumab in early-stage NSCLC.MethodsThis is a single-arm phase II study of perioperative pembrolizumab in patients with untreated, clinical stage IB to IIIA NSCLC. Patients received two doses of 200 mg pembrolizumab, surgery, standard adjuvant chemotherapy, followed by four doses adjuvant pembrolizumab. The primary objective of this study was to determine surgical feasibility rate, and secondary objectives are pathological response rate, treatment adverse events, efficacy data, and exploratory analysis of biomarkers.Results30 patients initiated perioperative pembrolizumab, and 25 completed tumor resection. At median follow-up of 59 months after surgical resection, seven patients had disease progression, while six had died representing. A 5-year progression-free survival (PFS) from time of surgery was 72.0% (56.4%–91.9%) and overall survival (OS) from time of surgery was 75.8% (60.7%–94.7%). Major pathological response (MPR) was found in seven tumors (28%) including two complete responses (4%). Across all treated patients, four receiving neoadjuvant and four receiving adjuvant pembrolizumab experienced treatment-related adverse events of grade 3 or higher with no grade 5 events. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels increased across our patient cohort over time from baseline until postsurgery and remained elevated at the end of treatment. There was a significant difference between mean plasma PCSK9 levels for patients with MPR versus all other patients on study when checked postoperatively.ConclusionsPerioperative pembrolizumab was safe and effective with promising MPR rate, PFS, and OS.

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 alleles (Onc-p53) exhibit significantly higher levels of proteasome activity, indicating that Onc-p53 induces proteotoxic stress which may be leveraged as a therapeutic vulnerability. Proteasome inhibitors (PIs), such as bortezomib (BTZ), can induce toxic levels of oxidative stress in cancer cells and thus we investigated whether PIs exhibit preferential cytotoxicity in Onc-p53 NSCLC cells. Indeed, BTZ and other PIs exhibited the IC50 6-7-fold lower in Onc-p53 cells vs. wild-type (WT) p53 cells. BTZ cytotoxic effects in Onc-p53 cells were nearly completely rescued by antioxidants such as N-acetyl 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 pro-apoptotic NOXA with downstream cleaved caspase-3, consistent with apoptotic cell death in Onc-p53 but not in WT p53 cells treated with BTZ, and 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 BTZ′s translational potential in Onc-p53 NSCLC, BTZ and carboplatin or the BH3-mimetic navitoclax were synergistically cytotoxic in Onc-p53 but not WT p53 cells in vitro, and BTZ effectively limited growth of Onc-p53 NSCLC xenografts when combined with either carboplatin or navitoclax in vivo. Our data therefore support further investigation of the therapeutic utility of PIs combined with carboplatin or BH3-mimetics in Onc-p53 human NSCLC as novel therapeutic strategies.Competing Interest StatementThe authors have declared no competing interest.