Ferroptosis: bug or feature? Dixon, Scott J.
Immunological reviews,
20/May , Volume:
277, Issue:
1
Journal Article
Peer reviewed
Summary
Ferroptosis is an iron‐dependent, oxidative form of non‐apoptotic cell death. This form of cell death does not share morphological, biochemical, or genetic similarities with classic necrosis, ...necroptosis, parthanatos, or other forms of non‐apoptotic cell death. Ferroptosis can be triggered by depleting the cell of the amino acid cysteine, or by inhibiting the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). Why certain stimuli trigger ferroptosis instead of another form of cell death, and whether this process could be adaptive in vivo, are two major unanswered questions concerning this process. Emerging evidence and consideration of related non‐apoptotic pathways suggest that ferroptosis could be an adaptive process, albeit one regulated and executed in a manner very different from apoptosis and other forms of cell death.
As urban space continues to expand to accommodate a growing global population, there remains a real need to quantify and qualify the impacts of urban space on natural processes. The expansion of ...global urban areas has resulted in marked alterations to natural processes, environmental quality and natural resource consumption. The urban landscape influences infiltration and evapotranspiration, complicating our capacity to quantify their dynamics across a heterogeneous landscape at contrasting scales. Impervious surfaces exacerbate runoff processes, whereas runoff from pervious areas remains uncertain owing to variable infiltration dynamics. Increasingly, the link between the natural hydrological cycle and engineered water cycle has been made, realising the contributions from leaky infrastructure to recharge and runoff rates. Urban landscapes are host to a suite of contaminants that impact on water quality, where novel contaminants continue to pose new challenges to monitoring and treatment regimes. This review seeks to assess the major advances and remaining challenges that remain within the growing field of urban hydrology.
Editor M.C. Acreman; Associate editor E. Rozos
Despite the success of colonoscopy screening, colorectal cancer (CRC) remains one of the most common and deadly cancers, and CRC incidence is rising in some countries where screening is not routine ...and populations have recently switched from traditional diets to western diets. Diet and energy balance influence CRC by multiple mechanisms. They modulate the composition and function of gut microbiota, which have a prodigious metabolic capacity and can produce oncometabolites or tumor‐suppressive metabolites depending, in part, on which dietary factors and digestive components are present in the GI tract. Gut microbiota also have a profound effect on immune cells in the lamina propria, which influences inflammation and subsequently CRC. Nutrient availability, which is an outcome of diet and energy balance, determines the abundance of certain energy metabolites that are essential co‐factors for epigenetic enzymes and therefore impinges upon epigenetic regulation of gene expression. Aberrant epigenetic marks accumulate during CRC, and epimutations that are selected for drive tumorigenesis by causing transcriptome profiles to diverge from the cell of origin. In some instances, the above mechanisms are intertwined as exemplified by dietary fiber being metabolized by colonic bacteria into butyrate, which is both a short‐chain fatty acid (SCFA) and a histone deacetylase (HDAC) inhibitor that epigenetically upregulates tumor‐suppressor genes in CRC cells and anti‐inflammatory genes in immune cells.
Diet and gut microbiota influence epigenetic events and colorectal cancer by multiple mechanisms. Microbiota convert dietary factors and digestive components into metabolites that positively or negatively influence cancer. These metabolites exert their effects in multiple ways including epigenetic regulation of gene expression as exemplified by butyrate functioning as an HDAC inhibitor. Gut microbiota also have a profound effect on immune cells, which influences colorectal cancer incidence and progression through the immune response. This is important not only for cancer prevention but also for cancer treatment as exemplified by recent work suggesting that probiotics will be a successful adjuvant for cancer immunotherapy.
Stroke is the fifth leading cause of death and a leading cause of disability in the United States, affecting nearly 800 000 individuals annually.
Sudden neurologic dysfunction caused by focal brain ...ischemia with imaging evidence of acute infarction defines acute ischemic stroke (AIS), while an ischemic episode with neurologic deficits but without acute infarction defines transient ischemic attack (TIA). An estimated 7.5% to 17.4% of patients with TIA will have a stroke in the next 3 months. Patients presenting with nondisabling AIS or high-risk TIA (defined as a score ≥4 on the age, blood pressure, clinical symptoms, duration, diabetes ABCD2 instrument; range, 0-7 7 indicating worst stroke risk), who do not have severe carotid stenosis or atrial fibrillation, should receive dual antiplatelet therapy with aspirin and clopidigrel within 24 hours of presentation. Subsequently, combined aspirin and clopidigrel for 3 weeks followed by single antiplatelet therapy reduces stroke risk from 7.8% to 5.2% (hazard ratio, 0.66 95% CI, 0.56-0.77). Patients with symptomatic carotid stenosis should receive carotid revascularization and single antiplatelet therapy, and those with atrial fibrillation should receive anticoagulation. In patients presenting with AIS and disabling deficits interfering with activities of daily living, intravenous alteplase improves the likelihood of minimal or no disability by 39% with intravenous recombinant tissue plasminogen activator (IV rtPA) vs 26% with placebo (odds ratio OR, 1.6 95% CI, 1.1-2.6) when administered within 3 hours of presentation and by 35.3% with IV rtPA vs 30.1% with placebo (OR, 1.3 95% CI, 1.1-1.5) when administered within 3 to 4.5 hours of presentation. Patients with disabling AIS due to anterior circulation large-vessel occlusions are more likely to be functionally independent when treated with mechanical thrombectomy within 6 hours of presentation vs medical therapy alone (46.0% vs 26.5%; OR, 2.49 95% CI, 1.76-3.53) or when treated within 6 to 24 hours after symptom onset if they have a large ratio of ischemic to infarcted tissue on brain magnetic resonance diffusion or computed tomography perfusion imaging (modified Rankin Scale score 0-2: 53% vs 18%; OR, 4.92 95% CI, 2.87-8.44).
Dual antiplatelet therapy initiated within 24 hours of symptom onset and continued for 3 weeks reduces stroke risk in select patients with high-risk TIA and minor stroke. For select patients with disabling AIS, thrombolysis within 4.5 hours and mechanical thrombectomy within 24 hours after symptom onset improves functional outcomes.
Summary Background Nivolumab has shown improved survival in the treatment of advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. We assessed the safety and activity of ...combination nivolumab plus ipilimumab as first-line therapy for NSCLC. Methods The open-label, phase 1, multicohort study (CheckMate 012) cohorts reported here were enrolled at eight US academic centres. Eligible patients were aged 18 years or older with histologically or cytologically confirmed recurrent stage IIIb or stage IV, chemotherapy-naive NSCLC. Patients were randomly assigned (1:1:1) by an interactive voice response system to receive nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks, or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicities, or withdrawal of consent. Data from the latter two cohorts, which were considered potentially suitable for further clinical development, are presented in this report; data from the other cohort (as well as several earlier cohorts) are described in the appendix . The primary outcome was safety and tolerability, assessed in all treated patients. This ongoing study is registered with ClinicalTrials.gov , number NCT01454102. Findings Between May 15, 2014, and March 25, 2015, 78 patients were randomly assigned to receive nivolumab every 2 weeks plus ipilimumab every 12 weeks (n=38) or nivolumab every 2 weeks plus ipilimumab every 6 weeks (n=40). One patient in the ipilimumab every-6-weeks cohort was excluded before treatment; therefore 77 patients actually received treatment (38 in the ipilimumab every-12-weeks cohort; 39 in the ipilimumab every-6-weeks cohort). At data cut-off on Jan 7, 2016, 29 (76%) patients in the ipilimumab every-12-weeks cohort and 32 (82%) in the ipilimumab every-6-weeks cohort had discontinued treatment. Grade 3–4 treatment-related adverse events occurred in 14 (37%) patients in the ipilimumab every-12-weeks cohort and 13 (33%) patients in the every-6-weeks cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (three 8% and no patients), pneumonitis (two 5% and one 3% patients), adrenal insufficiency (one 3% and two 5% patients), and colitis (one 3% and two 5% patients). Treatment-related serious adverse events were reported in 12 (32%) patients in the ipilimumab every-12-weeks cohort and 11 (28%) patients in the every-6-weeks cohort. Treatment-related adverse events (any grade) prompted treatment discontinuation in four (11%) patients in the every-12-weeks cohort and five (13%) patients in the every-6-weeks cohort. No treatment-related deaths occurred. Confirmed objective responses were achieved in 18 (47% 95% CI 31–64) patients in the ipilimumab every-12-weeks cohort and 15 (38% 95% CI 23–55) patients in the ipilimumab every-6-weeks cohort; median duration of response was not reached in either cohort, with median follow-up times of 12·8 months (IQR 9·3–15·5) in the ipilimumab every-12-weeks cohort and 11·8 months (6·7–15·9) in the ipilimumab every-6-weeks cohort. In patients with PD-L1 of 1% or greater, confirmed objective responses were achieved in 12 (57%) of 21 patients in the ipilimumab every-12-weeks cohort and 13 (57%) of 23 patients in the ipilimumab every-6-weeks cohort. Interpretation In NSCLC, first-line nivolumab plus ipilimumab had a tolerable safety profile and showed encouraging clinical activity characterised by a high response rate and durable response. To our knowledge, the results of this study are the first suggestion of improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC, supporting further assessment of this combination in a phase 3 study. Funding Bristol-Myers Squibb.
Apatinib Aitan
(brand name in China), also known as rivoceranib, is a novel, small molecule, selective vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor and is the ...second anti-angiogenic drug to be approved in China for the treatment of advanced or metastatic gastric cancer. This article summarizes the pharmacological properties of apatinib and reviews its clinical use in chemotherapy-experienced patients with advanced gastric adenocarcinoma, including gastroesophageal adenocarcinoma (GEA), or with other advanced cancers such as non-small cell lung cancer (NSCLC), breast cancer, gynaecological cancers, hepatocellular carcinoma (HCC), thyroid cancer and sarcomas. As third- or subsequent-line therapy, oral apatinib significantly prolonged median progression-free survival (PFS) and overall survival (OS) compared with placebo and had a manageable safety profile in Chinese patients with advanced or metastatic gastric cancer or GEA participating in randomized, double-blind, multicentre, phase 2 and 3 trials. More limited evidence also supports it use as subsequent-line treatment in Chinese patients with other advanced or metastatic solid tumours, including NSCLC, breast cancer and HCC. Further clinical experience and long-term pharmacovigilance data are required to more definitively establish the efficacy and safety profile of apatinib, including its use in combination with other chemotherapy agents and its role in the management of other types of advanced or metastatic solid tumours. In the meantime, given its convenient administration regimen and the limited treatment options and poor prognosis for patients with advanced or metastatic solid tumours, apatinib is an important, emerging treatment option for adult patients with advanced gastric adenocarcinoma or GEA who have progressed or relapsed after chemotherapy.
Mechanisms of ferroptosis Cao, Jennifer Yinuo; Dixon, Scott J.
Cellular and molecular life sciences : CMLS,
06/2016, Volume:
73, Issue:
11-12
Journal Article
Peer reviewed
Open access
Ferroptosis is a non-apoptotic form of cell death that can be triggered by small molecules or conditions that inhibit glutathione biosynthesis or the glutathione-dependent antioxidant enzyme ...glutathione peroxidase 4 (GPX4). This lethal process is defined by the iron-dependent accumulation of lipid reactive oxygen species and depletion of plasma membrane polyunsaturated fatty acids. Cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression may be sensitized to this process. Conversely, a number of small molecule inhibitors of ferroptosis have been identified, including ferrostatin-1 and liproxstatin-1, which can block pathological cell death events in brain, kidney and other tissues. Recent work has identified a number of genes required for ferroptosis, including those involved in lipid and amino acid metabolism. Outstanding questions include the relationship between ferroptosis and other forms of cell death, and whether activation or inhibition of ferroptosis can be exploited to achieve desirable therapeutic ends.
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