Melanoma is a malignant neoplasm of melanocytes that accounts for the majority of skin cancer deaths despite comprising less than 5% of all cutaneous malignancies. Its incidence has increased faster ...than that of any other cancer over the past half-century and the annual costs of treatment in the United States alone have risen rapidly. Although the majority of primary melanomas are cured with local excision, metastatic melanoma historically carries a grim prognosis, with a median survival of 9 months and a long-term survival rate of 10%. Given the urgent need to develop treatment strategies for metastatic melanoma and the explosion of genetic technologies over the past 20 years, there has been extensive research into the genetic alterations that cause melanocytes to become malignant. More recently, efforts have focused on the genetic changes that drive melanoma metastasis. This review aims to summarize the current knowledge of the genetics of primary cutaneous and ocular melanoma, the genetic changes associated with metastasis in melanoma and other cancer types, and non-genetic factors that may contribute to metastasis.
The Greenland Ice Sheet has been a major contributor to global sea-level rise in recent decades
, and it is expected to continue to be so
. Although increases in glacier flow
and surface melting
have ...been driven by oceanic
and atmospheric
warming, the magnitude and trajectory of the ice sheet's mass imbalance remain uncertain. Here we compare and combine 26 individual satellite measurements of changes in the ice sheet's volume, flow and gravitational potential to produce a reconciled estimate of its mass balance. The ice sheet was close to a state of balance in the 1990s, but annual losses have risen since then, peaking at 345 ± 66 billion tonnes per year in 2011. In all, Greenland lost 3,902 ± 342 billion tonnes of ice between 1992 and 2018, causing the mean sea level to rise by 10.8 ± 0.9 millimetres. Using three regional climate models, we show that the reduced surface mass balance has driven 1,964 ± 565 billion tonnes (50.3 per cent) of the ice loss owing to increased meltwater runoff. The remaining 1,938 ± 541 billion tonnes (49.7 per cent) of ice loss was due to increased glacier dynamical imbalance, which rose from 46 ± 37 billion tonnes per year in the 1990s to 87 ± 25 billion tonnes per year since then. The total rate of ice loss slowed to 222 ± 30 billion tonnes per year between 2013 and 2017, on average, as atmospheric circulation favoured cooler conditions
and ocean temperatures fell at the terminus of Jakobshavn Isbræ
. Cumulative ice losses from Greenland as a whole have been close to the rates predicted by the Intergovernmental Panel on Climate Change for their high-end climate warming scenario
, which forecast an additional 70 to 130 millimetres of global sea-level rise by 2100 compared with their central estimate.
Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ...ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer’s, Huntington’s, and Parkinson’s diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
This Primer reviews the mechanisms, tools, and guidelines to study ferroptosis, a form of cell death that is emerging as a central player in several degenerative diseases.
The ductal system of the salivary gland has long been postulated to be resistant to radiation-induced damage, a common side effect incurred by head and neck cancer patients receiving radiotherapy. ...Yet, whether the ducts are capable of regenerating after genotoxic injury, or whether damage to ductal cells induces lineage plasticity, as has been reported in other organ systems, remains unknown. Here, using the murine salivary gland, we show that two ductal progenitor populations, marked exclusively by KRT14 and KIT, maintain non-overlapping ductal compartments after radiation exposure but do so through distinct cellular mechanisms. KRT14
progenitor cells are fast-cycling cells that proliferate in response to radiation-induced damage in a sustained manner and divide asymmetrically to produce differentiated cells of the larger granulated ducts. Conversely, KIT
intercalated duct cells are long-lived progenitors for the intercalated ducts that undergo few cell divisions either during homeostasis or after gamma radiation, thus maintaining ductal architecture with slow rates of cell turnover. Together, these data illustrate the regenerative capacity of the salivary ducts and highlight the heterogeneity in the damage responses used by salivary progenitor cells to maintain tissue architecture.
Summary
Background
In pancreatic ductal adenocarcinoma (PDAC), the chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-C motif) receptor 2 (CCR2) axis plays a key role in immunosuppressive properties ...of the tumor microenvironment, patient prognosis, and chemoresistance. This phase Ib study assessed the effects of the orally administered CCR2 inhibitor PF-04136309 in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic PDAC.
Methods
Patients received PF-04136309 twice daily (BID) continuously plus nab-paclitaxel (125 mg/m
2
) and gemcitabine (1000 mg/m
2
) administered on days 1, 8, and 15 of each 28-day cycle. The primary objectives were to evaluate safety and tolerability, characterize dose-limiting toxicities (DLTs), and determine the recommended phase II dose (RP2D) of PF-04136309.
Results
In all, 21 patients received PF-04136309 at a starting dose of 500 mg or 750 mg BID. The RP2D was identified to be 500 mg BID. Of 17 patients treated at the 500 mg BID starting dose, three (17.6%) experienced a total of four DLTs, including grade 3 dysesthesia, diarrhea, and hypokalemia and one event of grade 4 hypoxia.
Relative to the small number of patients (n = 21), a high incidence (24%) of pulmonary toxicity was observed in this study.
The objective response rate for 21 patients was 23.8% (95% confidence interval: 8.2–47.2%). Levels of CD14 + CCR2+ inflammatory monocytes (IM) decreased in the peripheral blood, but did not accumulate in the bone marrow.
Conclusions
PF-04136309 in combination with nab-paclitaxel plus gemcitabine had a safety profile that raises concern for synergistic pulmonary toxicity and did not show an efficacy signal above nab-paclitaxel and gemcitabine.
ClinicalTrials.gov
identifier: NCT02732938.
Advanced pancreatic cancer remains one of the deadliest malignancies in 2022. Although there has been significant progress in treatment options with improved outcomes in many cancers, this growth has ...been slow in pancreatic cancer. This article examines specific components of approved first- and second-line therapies for advanced pancreatic cancer treatment and their effectiveness and concludes with a brief exploration of future directions for targeted therapies.
Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one
(cystic fibrosis transmembrane conductance ...regulator) allele, but it has not been evaluated in children <12 years of age.
To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with
-minimal function or
-
genotypes.
In this 24-week open-label phase 3 study, children (
= 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h).
The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV
(10.2 percentage points; 95% confidence interval CI, 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index
(-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age
-score increased over the 24-week treatment period when compared with the pretreatment baseline.
Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one
allele, supporting its use in this patient population. Clinical trial registered with www.clinicaltrials.gov (NCT03691779).
Background
Older adults receiving cancer therapy have heightened risk for treatment-related toxicity. Geriatric assessment (GA) can identify impairments, which may contribute to vulnerability and ...adverse outcomes. GA management interventions can address these impairments and have the potential to improve outcomes when implemented.
Methods
We conducted a randomized pilot study comparing GA with management interventions versus usual care in patients with stage III/IV solid tumor malignancies (
N
= 71). In all patients, a trained coordinator conducted and scored a baseline GA with pre-determined cutoffs for impairment. For patients randomized to the intervention arm, an algorithm was used to identify GA management recommendations based upon identified impairments. Recommendations were relayed to the primary oncologist for implementation. GA was repeated at 3 months. The primary outcome was grade 3–5 chemotherapy toxicity. Secondary outcomes included feasibility, hospitalizations, dose reductions, dose delays, and early treatment discontinuation.
Results
The mean participant age was 76 (70–89). The total number of GA management recommendations relayed was 409, of which 35.4% were implemented by the primary oncologist. Incidence of grade 3–5 chemotherapy toxicity did not differ between the two groups. Prevalence of hospitalization, dose reductions, dose delays, and early treatment discontinuation also did not differ between the two groups.
Conclusions
An algorithm can be used to guide GA management recommendations in older adults with cancer. However, reliance upon the primary oncologist for execution resulted in a low prevalence of implementation. Future work should aim to understand barriers to implementation and explore alternate models of implementing geriatric-focused care for older adults with cancer.
Literature reviewed suggests energy maturity models are in their infancy in the energy management sector, with little practical guidance for their implementation in multi-site organisations. In ...addressing this gap, this paper presents the development and implementation of an Energy Management Maturity Model for multi-site industrial organisations with a global presence, considered as a fundamental step towards continuous improvement and optimal energy efficiency. The developed maturity model provides a global view of the overall network readiness for engaging in energy efficiency by adapting and enhancing existing ‘site focused’ maturity models to cater for a multi-site industrial organisation. The model enables two-way communication between global and local energy management teams; not only are the individual sites benchmarked but the global energy management team receives feedback and a gap analysis on their performance from the network of sites perspective. The evaluation framework created around the maturity model supports automated prioritization of elements with larger deviations from the site and network median score. In parallel it provides the global energy management team with direction on where the organisation needs to focus central efforts to support the individual sites. The maturity model enables the evaluation of key non-technical aspects of energy management required for continuous improvement on a multi-site and global scale.
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