Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic ...breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance.
Tissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival.
Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C.
We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET.
ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.
Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced cancers. However, the tumor microenvironment (TME) functions as a formidable barrier that ...severely impairs the efficacy of ICIs. While the crosstalk between tumor vessels and immune cells determines the nature of anti-tumor immunity, it is skewed toward a destructive cycle in growing tumors. First, the disorganized tumor vessels hinder CD8
T cell trafficking into the TME, disable effector functions, and even kill T cells. Moreover, VEGF, the key driver of angiogenesis, interferes with the maturation of dendritic cells, thereby suppressing T cell priming, and VEGF also induces TOX-mediated exhaustion of CD8
T cells. Meanwhile, a variety of innate and adaptive immune cells contribute to the malformation of tumor vessels. Protumoral M2-like macrophages as well as T
2 and Treg cells secrete pro-angiogenic factors that accelerate uncontrolled angiogenesis and promote vascular immaturity. While CD8
T and CD4
T
1 cells suppress angiogenesis and induce vascular maturation by secreting IFN-γ, they are unable to infiltrate the TME due to malformed tumor vessels. These findings led to preclinical studies that demonstrated that simultaneous targeting of tumor vessels and immunity is a viable strategy to normalize aberrant vascular-immune crosstalk and potentiate cancer immunotherapy. Furthermore, this combination strategy has been evidently demonstrated through recent pivotal clinical trials, granted approval from FDA, and is now being used in patients with kidney, liver, lung, or uterine cancer. Overall, combining anti-angiogenic therapy and ICI is a valid therapeutic strategy that can enhance cancer immunity and will further expand the landscape of cancer treatment.
A spiking neural network (SNN) inspired by the structure and principles of the human brain can significantly enhance the energy efficiency of artificial intelligence computing by overcoming the ...bottlenecks of the conventional von Neumann architecture with its massive parallelism and spike transmissions. The construction of artificial neurons is important for the hardware implementation of an SNN, which generates spike signals when enough synaptic signals are gathered. Because circuit‐level artificial neurons with comparator and reset circuits require considerable hardware area, intensive efforts are devoted in recent years for building artificial neurons at the device level for better area efficiency. Furthermore, artificial sensory neuron devices, which perform neural processing and sensing concurrently, have recently been developed in order to reduce the hardware cost and energy consumption of traditional sensory systems through in‐sensor computing. This review article surveys and benchmarks the recent progress of artificial neuron devices for neural processing and sensing. First, various artificial neuron devices are summarized, including single‐transistor neurons (1T‐neurons), memristor neurons, phase‐change neurons, magnetic neurons, and ferroelectric neurons. Next, cointegration technologies with artificial synaptic devices and artificial sensory neurons for in‐sensor computing are introduced. Finally, the challenges and prospects for developing artificial neuron devices are discussed.
The recent progress in artificial neuron devices for neural processing and sensing in a bioinspired spiking neural network is reviewed. Various artificial neuron devices with spiking operation, corresponding cointegration technologies with artificial synaptic devices, and recently emerging artificial sensory neurons for low‐power in‐sensor computing are addressed.
Obesity increases the risks of diabetes, hypertension, and cardiovascular diseases, ultimately contributing to mortality. Korean Society for the Study of Obesity (KSSO) was established to improve the ...management of obesity through research and education; to that end, the Committee of Clinical Practice Guidelines of KSSO reviews systemic evidence using expert panels to develop clinical guidelines. The clinical practice guidelines for obesity were revised in 2018 using National Health Insurance Service Health checkup data from 2006 to 2015. Following these guidelines, we added a category, class III obesity, which includes individuals with body mass index (BMI) ≥35 kg/m
. Agreeing with the International Federation for the Surgery of Obesity and Metabolic Disorders, Asian Pacific Chapter consensus, we determined that bariatric surgery is indicated for Korean patients with BMI ≥35 kg/m
and for Korean patients with BMI ≥30 kg/m
who have comorbidities. The new guidelines focus on guiding clinicians and patients to manage obesity more effectively. Our recommendations and treatment algorithms can serve as a guide for the evaluation, prevention, and management of overweight and obesity.
Spintronics relies on magnetization switching through current-induced spin torques. However, because spin transfer torque for ferromagnets is a surface torque, a large switching current is required ...for a thick, thermally stable ferromagnetic cell, and this remains a fundamental obstacle for high-density non-volatile applications with ferromagnets. Here, we report a long spin coherence length and associated bulk-like torque characteristics in an antiferromagnetically coupled ferrimagnetic multilayer. We find that a transverse spin current can pass through >10-nm-thick ferrimagnetic Co/Tb multilayers, whereas it is entirely absorbed by a 1-nm-thick ferromagnetic Co/Ni multilayer. We also find that the switching efficiency of Co/Tb multilayers partially reflects a bulk-like torque characteristic, as it increases with ferrimagnet thickness up to 8 nm and then decreases, in clear contrast to the 1/thickness dependence of ferromagnetic Co/Ni multilayers. Our results on antiferromagnetically coupled systems will invigorate research towards the development of energy-efficient spintronics.
Background
There is lack of data on effect modification by age on the association between body mass index (BMI) or waist circumference (WC) and cardiovascular diseases (CVDs). We aimed to investigate ...the impact of BMI and WC on incident CVDs in individuals aged 40 and 66 years.
Methods
Overall, 2 430 510 participants who underwent a national health screening for transitional ages provided by the Korean National Health Insurance Service between 2009 and 2012 were included. The adjusted hazard ratios and 95% confidence intervals for myocardial infarction (MI), ischaemic stroke and CVDs as a composite outcome of MI and ischaemic stroke were calculated using multivariable Cox proportional hazard regression analysis.
Results
During a mean follow‐up of 7.7 years, 24 884 MI and 29 415 ischaemic stroke events occurred. Among participants aged 40 years, there was a J‐shaped association of BMI with incident CVDs, MI and ischaemic stroke with nadir at BMI 18.5–22.9 kg/m2 (P for trend < 0.001 for all). Among those aged 66 years, there were significant U‐shaped associations of BMI with CVDs and MI with nadir at a BMI of 23.0–24.9 kg/m2 (P for trend 0.013 and 0.017, respectively). WC was linearly associated with all study outcomes in both age groups (P for trend < 0.001). The impact of general and abdominal obesity on both study outcomes was more prominent in those aged 40 years than in those aged 66 years (P for interaction < 0.001).
Conclusions
To prevent cardiovascular risk, weight loss intervention should be cautiously implemented and individualized according to age. The maintenance of muscle mass may be essential in managing weight loss particularly in older population.
Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti–programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) ...investigated osimertinib plus durvalumab versus osimertinib monotherapy in patients with EGFR-TKI sensitizing and EGFR T790M mutation–positive advanced NSCLC and disease progression after EGFR-TKI therapy.
Patients were randomly assigned 1:1 to receive orally administered osimertinib (80 mg once daily) with or without durvalumab (10 mg/kg administered intravenously every 2 weeks) until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by the investigator). The amended primary objective was to assess the safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective.
CAURAL recruitment was terminated early because of increased incidence of interstitial lung disease–like events in the osimertinib plus durvalumab arm from the separate phase Ib TATTON trial (NCT02143466). At termination of CAURAL recruitment, 15 patients had been randomly assigned to treatment with osimertinib and 14 to treatment with osimertinib plus durvalumab. The most common AEs were diarrhea (53% grade ≥3 in 6% of patients) in the osimertinib arm and rash (67% grade ≥3 in 0 patients) in the combination arm. One patient who had been randomized to the combination arm reported grade 2 interstitial lung disease while receiving osimertinib monotherapy (after discontinuing durvalumab therapy after one dose). The objective response rates were 80% in the osimertinib arm and 64% in the combination arm.
Limited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of programmed cell death 1/programmed death ligand 1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but it requires a careful approach if considered in the future.
Nonclassical features of crystallization in solution have been recently identified both experimentally and theoretically. In particular, an amorphous-phase-mediated pathway is found in various ...crystallization systems as an important route, different from the classical nucleation and growth model. Here, we utilize high-resolution in situ transmission electron microscopy with graphene liquid cells to study amorphous-phase-mediated formation of Ni nanocrystals. An amorphous phase is precipitated in the initial stage of the reaction. Within the amorphous particles, crystalline domains nucleate and eventually form nanocrystals. In addition, unique crystallization behaviors, such as formation of multiple domains and dislocation relaxation, are observed in amorphous-phase-mediated crystallization. Theoretical calculations confirm that surface interactions can induce amorphous precipitation of metal precursors, which is analogous to the surface-induced amorphous-to-crystalline transformation occurring in biomineralization. Our results imply that an unexplored nonclassical growth mechanism is important for the formation of nanocrystals.
We report proteogenomic analysis of diffuse gastric cancers (GCs) in young populations. Phosphoproteome data elucidated signaling pathways associated with somatic mutations based on ...mutation-phosphorylation correlations. Moreover, correlations between mRNA and protein abundances provided potential oncogenes and tumor suppressors associated with patient survival. Furthermore, integrated clustering of mRNA, protein, phosphorylation, and N-glycosylation data identified four subtypes of diffuse GCs. Distinguishing these subtypes was possible by proteomic data. Four subtypes were associated with proliferation, immune response, metabolism, and invasion, respectively; and associations of the subtypes with immune- and invasion-related pathways were identified mainly by phosphorylation and N-glycosylation data. Therefore, our proteogenomic analysis provides additional information beyond genomic analyses, which can improve understanding of cancer biology and patient stratification in diffuse GCs.
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•Mutation-phosphorylation correlation suggests possible signaling interplays in EOGCs•mRNA-protein correlation suggests genes with high association with patient survival•Integrated analysis of mRNA and protein data identified four subtypes•Phosphorylation data provide cellular signaling pathways underlying the subtypes
Mun et al. perform proteogenomic analysis of diffuse gastric cancers (DGC) in a young population, identifying that correlations of mRNA-protein abundance associate with survival and defining four subtypes of DGC. The associations of some subtypes with related pathways are identified mainly by the proteomic data.
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