Cutaneous melanoma Eggermont, Alexander MM, Prof; Spatz, Alan, MD; Robert, Caroline, MD
The Lancet (British edition),
03/2014, Volume:
383, Issue:
9919
Journal Article
Peer reviewed
Summary In the past decade, major advances have been made in the understanding of melanoma. New predisposition genes have been reported and key somatic events, such as BRAF mutation, directly ...translated into therapeutic management. Surgery for localised melanoma and regional lymph node metastases is the standard of care. Sentinel-node biopsy provides precise staging, but has not been reported to affect survival. The effect of lymph-node dissection on survival is a topic of investigation. Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF -mutated melanoma. The combination of BRAF inhibitors and MEK inhibitors might improve progression-free survival further and, possibly, increase overall survival. Response patterns differ substantially—anti-CTLA4 immunotherapy can induce long-term responses, but only in a few patients, whereas targeted drugs induce responses in most patients, but nearly all of them relapse because of pre-existing or acquired resistance. Thus, the long-term prognosis of metastatic melanoma remains poor. Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability. Biomarkers that have predictive value remain elusive in melanoma, although emerging data for adjuvant therapy indicate that interferon sensitivity is associated with ulceration of the primary melanoma. Intense investigation continues for clinical and biological markers that predict clinical benefit of immunotherapeutic drugs, such as interferon alfa or anti-CTLA4 antibodies, and the mechanisms that lead to resistance of targeted drugs.
Ferroptosis, a newly emerged form of regulated necrotic cell death, has been demonstrated to play an important role in multiple diseases including cancer, neurodegeneration, and ischemic organ ...injury. Mounting evidence also suggests its potential physiological function in tumor suppression and immunity. The execution of ferroptosis is driven by iron-dependent phospholipid peroxidation. As such, the metabolism of biological lipids regulates ferroptosis via controlling phospholipid peroxidation, as well as various other cellular processes relevant to phospholipid peroxidation. In this review, we provide a comprehensive analysis by focusing on how lipid metabolism impacts the initiation, propagation, and termination of phospholipid peroxidation; how multiple signal transduction pathways communicate with ferroptosis via modulating lipid metabolism; and how such intimate cross talk of ferroptosis with lipid metabolism and related signaling pathways can be exploited for the development of rational therapeutic strategies.
In this review, Liang et al. describe the recent development on the pivotal role of lipid metabolism, as well as various signaling pathways that modulate lipid metabolism, in ferroptosis. They also highlight some unanswered questions in the field and suggest potential ferroptosis induction-based cancer therapeutic strategies.
Highlights • Intestinal microbiota plays a crucial role in the host’s aging process. • Healthspan-promoting interventions are accompanied by normalization of gut microbiota. • Microbiota-targeted ...intervention is a promising anti-aging treatment option.
Mechanical surface modification such as shot peening offer powerful enhancement of fatigue properties of metals and other materials. Cavitation usually causes surface damage in hydraulic machineries. ...However, careful selection of process parameters allowed developing an approach known as “cavitation peening.” Its advantage is surface roughness increase is lower than in conventional shot peening as there are no solid collisions involved. As cavitation is a hydrodynamic phenomenon, an understanding of both fluid dynamics and materials science is required. Cavitation peening is distinguished from “water jet peening,” in which water column impulse is used. Another flavor is “Submerged laser peening” that involves the use of a pulsed laser and can be considered a type of cavitation peening where cavitating bubbles are generated due to laser ablation. Ultrasound vibration, a popular method for generating cavitation for cleaning, has also been adapted for cavitation peening. The present comparative review presents key insights and achievements and addresses future directions that are required for advancing cavitation peening technology by considering the mechanisms of cavitation peening based on the reported data for water jet, pulsed laser, and ultrasonic cavitation peening. The data and methods are critically considered and summarized in comparison with shot peening. Strategic view of future challenges is presented.
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•Fatigue resistance enhancement using water jet, pulsed laser and ultrasonic cavitation peening was quantified•Cavitation peening using jet, pulsed laser & ultrasonic enhanced fatigue properties•Cavitation peening clearly distinguished from water jet peening•Cavitation peening benefits shown to exceed those by shot peening•Dislocation density induced by cavitation peening was lower than by shot peening•Importance of vortex cavitation is shown for experimental and numerical future work
Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and ...pathologic features are poorly described. Methods Patients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher's exact test as were associations between pneumonitis features and outcomes. Results Of 915 patients who received anti-PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 5%; Melanoma Institute of Australia, 16 of 337 5%). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 10% v 24 of 716 3%; P < .01). Incidence was similar in patients with melanoma and non-small-cell lung cancer (overall, 26 of 532 5% v nine of 209 4%; monotherapy, 15 of 417 v five of 152 P = 1.0; combination, 11 of 115 v four of 57 P = .78). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion Pneumonitis associated with anti-PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti-PD-1/PD-L1 mAbs are combined with anti-cytotoxic T-cell lymphocyte-4 mAb. Most events are low grade and improve/resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.
The Pd‐catalyzed coupling of aryl (pseudo)halides and amines is one of the most powerful approaches for the formation of C(sp2)−N bonds. The pioneering reports from Migita and subsequently Buchwald ...and Hartwig on the coupling of aminostannanes and aryl bromides rapidly evolved into general and practical tin‐free protocols with broad substrate scope, which led to the establishment of what is now known as the Buchwald–Hartwig amination. This Minireview summarizes the evolution of this cross‐coupling reaction over the course of the past 25 years and illustrates some of the most recent applications of this well‐established methodology.
The first quarter century: The Buchwald–Hartwig amination enables the formation of C(sp2)−N bonds through the Pd‐catalyzed coupling of (hetero)aryl halides and pseudohalides with amines. This Minireview discusses the development of this methodology over the past 25 years, including highlights of some of the most recent applications.
Mitochondrial fission and fusion play critical roles in maintaining functional mitochondria when cells experience metabolic or environmental stresses. Fusion helps mitigate stress by mixing the ...contents of partially damaged mitochondria as a form of complementation. Fission is needed to create new mitochondria, but it also contributes to quality control by enabling the removal of damaged mitochondria and can facilitate apoptosis during high levels of cellular stress. Disruptions in these processes affect normal development, and they have been implicated in neurodegenerative diseases, such as Parkinson's.
Research pertaining to conductive polymers has gained significant traction in recent years, and their applications range from optoelectronics to material science. For all intents and purposes, ...conductive polymers can be described as Nobel Prize-winning materials, given that their discoverers were awarded the Nobel Prize in Chemistry in 2000. In this review, we seek to describe the chemical forms and functionalities of the main types of conductive polymers, as well as their synthesis methods. We also present an in-depth analysis of composite conductive polymers that contain various nanomaterials such as graphene, fullerene, carbon nanotubes, and paramagnetic metal ions. Natural polymers such as collagen, chitosan, fibroin, and hydrogel that are structurally modified for them to be conductive are also briefly touched upon. Finally, we expound on the plethora of biomedical applications that harbor the potential to be revolutionized by conductive polymers, with a particular focus on tissue engineering, regenerative medicine, and biosensors.
Lipid-based nanocarriers or liposomes have been proven successful in the delivery of chemotherapeutic agents and are currently applied clinically in the treatment of various types of cancer. ...Liposomes offer the advantage of a high drug payload, decreased drug toxicity and enhanced drug accumulation at tumor sites. Increased accumulation is due to the relatively leaky tumor vasculature that allows liposome extravasation. Between different types of tumors and even within one tumor, vascular permeability and thus liposome extravasation may differ greatly. Furthermore, upon accumulation of liposomes in the tumor area, drug bioavailability is not guaranteed. At present, these are the major issues for clinically used liposomal drugs. Mild hyperthermia (HT), the heating of tumor tissue to temperatures of up to 43°C, has been developed in the past decades as an established and efficacious treatment modality in combination with chemo- and radiotherapy. HT can be used to further improve liposomal chemotherapy in two ways: HT is known to increase vascular permeability in solid tumors and may therefore increase levels of liposome accumulation, and thermosensitive liposomes have been developed that can be triggered to release their contents upon hyperthermia. By applying these two strategies, drug delivery to tumors can be strongly enhanced.
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