In order to ascertain the impact of a biomarker-based (personalized) strategy, we compared outcomes between US Food and Drug Administration (FDA)-approved cancer treatments that were studied with and ...without such a selection rationale.
Anticancer agents newly approved (September 1998 to June 2013) were identified at the Drugs@FDA website. Efficacy, treatment-related mortality, and hazard ratios (HRs) for time-to-event endpoints were analyzed and compared in registration trials for these agents. All statistical tests were two-sided.
Fifty-eight drugs were included (leading to 57 randomized 32% personalized and 55 nonrandomized trials 47% personalized, n = 38 104 patients). Trials adopting a personalized strategy more often included targeted (100% vs 65%, P < .001), oral (68% vs 35%, P = .001), and single agents (89% vs 71%, P = .04) and more frequently permitted crossover to experimental treatment (67% vs 28%, P = .009). In randomized registration trials (using a random-effects meta-analysis), personalized therapy arms were associated with higher relative response rate ratios (RRRs, compared with their corresponding control arms) (RRRs = 3.82, 95% confidence interval CI = 2.51 to 5.82, vs RRRs = 2.08, 95% CI = 1.76 to 2.47, adjusted P = .03), longer PFS (hazard ratio HR = 0.41, 95% CI = 0.33 to 0.51, vs HR = 0.59, 95% CI = 0.53 to 0.65, adjusted P < .001) and a non-statistically significantly longer OS (HR = 0.71, 95% CI = 0.61 to 0.83, vs HR = 0.81, 95% CI = 0.77 to 0.85, adjusted P = .07) compared with nonpersonalized trials. Analysis of experimental arms in all 112 registration trials (randomized and nonrandomized) demonstrated that personalized therapy was associated with higher response rate (48%, 95% CI = 42% to 55%, vs 23%, 95% CI = 20% to 27%, P < .001) and longer PFS (median = 8.3, interquartile range IQR = 5 vs 5.5 months, IQR = 5, adjusted P = .002) and OS (median = 19.3, IQR = 17 vs 13.5 months, IQR = 8, Adjusted P = .04). A personalized strategy was an independent predictor of better RR, PFS, and OS, as demonstrated by multilinear regression analysis. Treatment-related mortality rate was similar for personalized and nonpersonalized trials.
A biomarker-based approach was safe and associated with improved efficacy outcomes in FDA-approved anticancer agents.
The persistent energy imbalance at the top of the atmosphere, inferred from satellite measurements, indicates that the Earth's climate system continues to accumulate excess heat. As only sparse and ...irregular measurements of ocean heat below 2000 m depth exist, one of the most challenging questions in global climate change studies is whether the excess heat has already penetrated into the deep ocean. Here we perform a comprehensive analysis of satellite and in situ measurements to report that a significant deep‐ocean warming occurred in the subtropical South Pacific Ocean over the past decade (2005–2014). The local accumulation of heat accounted for up to a quarter of the global ocean heat increase, with directly and indirectly inferred deep ocean (below 2000 m) contribution of 2.4 ± 1.4 and 6.1–10.1 ± 4.4%, respectively. We further demonstrate that this heat accumulation is consistent with a decade‐long intensification of the subtropical convergence, possibly linked to the persistent La Niña‐like state.
Key Points
Subtropical South Pacific is one of the Earth's major heat accumulators and accounts for up to a quarter of the global ocean heat increase
Indirect and direct estimates based on satellite and in situ data show significant local heat accumulation below 2000 m depth
Heat accumulation is due to a decade‐long intensification of wind‐driven convergence possibly linked to persistent La Niña‐like conditions
The low‐amplitude, large‐scale, interannual, and longer‐term sea level changes are linked to the variations of ocean heat and freshwater content and strongly controlled by ocean dynamics. Near the ...coast, especially in low‐lying and flood‐vulnerable regions, these changes can provide background conditions favorable for the occurrence of extreme sea levels that represent a threat for coastal communities and ecosystems. In this study, we identify a tripole mode of the ocean gyre‐scale sea surface height variability in the North Atlantic and show that this mode is responsible for most of the interannual‐to‐decadal sea surface height changes along the southeast coast of the United States, including the Gulf of Mexico. We also show that these changes are largely driven by the large‐scale heat divergence related to the Atlantic Meridional Overturning Circulation and linked to the low‐frequency North Atlantic Oscillation.
Plain Language Summary
The global mean sea level rise caused by ocean warming and terrestrial glacier melting is one of the most alarming aspects of climate change. However, ocean and atmosphere dynamics make sea level change spatially and temporally nonuniform. In fact, the ocean exhibits certain patterns of sea level change with alternating signs over different time periods. These patterns provide background conditions, on top of which shorter‐period and often stronger weather‐driven sea level fluctuations are superimposed. In order to improve our capacity to predict regional sea level variability, it is important to identify these patterns and to explore the mechanisms responsible for their evolution. In this study, we identify such a pattern in the North Atlantic Ocean and show that it is largely responsible for year‐to‐year changes of coastal sea level south of Cape Hatteras and in the Gulf of Mexico. These coastal regions of the United States are particularly vulnerable to extreme weather conditions, such as tropical storms and hurricanes, that can cause catastrophic flooding. We show that the temporal evolution of the identified pattern is due to the basin‐scale ocean heat content changes in the North Atlantic, driven by changes in the large‐scale ocean and atmosphere circulations.
Key Points
Interannual sea surface height variability in the North Atlantic exhibits a tripole pattern
The sea surface height tripole explains up to 60–80% of interannual sea level variance along the southeast U.S. coast and in the Gulf of Mexico
The tripole is associated with gyre‐scale heat divergence in response to low‐frequency North Atlantic Oscillation
Background
The phosphatidylinositol 3‐kinase (PI3K) pathway is frequently altered in cancer. This report describes the landscape of PI3K alterations in solid tumors as well as co‐alterations serving ...as potential resistance/attenuation mechanisms.
Methods
Consecutive samples were analyzed in a commercial Clinical Laboratory Improvement Amendment‐certified laboratory using comprehensive genomic profiling performed by next‐generation sequencing (315 genes). The co‐alterations evaluated included the Erb‐B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, RAS, MET proto‐oncogene tyrosine kinase (MET), and mitogen‐activated protein kinase kinase (MAP2K) genes as well as tumor protein 53 (TP53), estrogen receptor 1 (ESR1), and androgen receptor (AR).
Results
Alterations in any of 18 PI3K‐pathway associated genes were identified in 44% of 60,991 tumors. Although single base and insertions/deletions (indels) were the most frequent alterations, copy number changes and rearrangements were identified in 11% and 0.9% of patients, respectively. Overall, the most frequently altered genes were PIK3 catalytic subunit α (PIK3CA) (13%), phosphatase and tensin homolog (PTEN) (9%), and serine/threonine kinase 11 (STK11) (5%). Tumor types that frequently harbored at least 1 PI3K alteration were uterine (77%), cervical (62%), anal (59%), and breast (58%) cancers. Alterations also were discerned frequently in tumors with carcinosarcoma (89%) and squamous cell carcinoma (62%) histologies. Tumors with a greater likelihood of co‐occurring PI3K pathway and MAPK pathway alterations included colorectal cancers (odds ratio OR, 1.64; P < .001), mesotheliomas (OR, 2.67; P = .024), anal cancers (OR, 1.98; P = .03), and nonsquamous head and neck cancers (OR, 2.03; P = .019). The co‐occurrence of ESR1 and/or AR alterations with PI3K alterations was statistically significant in bladder, colorectal, uterine, prostate, and unknown primary cancers.
Conclusions
Comprehensive genomic profiling reveals altered PI3K‐related genes in 44% of solid malignancies, including rare disease and histology types. The frequency of alterations and the co‐occurrence of resistance pathways vary by tumor type, directly affecting opportunities for targeted therapy.
Comprehensive genomic profiling of solid tumors reveals frequent genetic alterations in several genes of the phosphatidylinositol 3‐kinase (PI3K) pathway. Data from this analysis suggest that in‐depth characterization of the PI3K pathway along with concomitant resistance alterations in other pathways can provide a genomic background for the development of future treatments.
A global ocean data synthesis product at eddy‐permitting resolution from Estimating the Circulation and Climate of the Ocean, Phase II (ECCO2) project are used to estimate the oceanic eddy heat ...transport. We show that in a number of locations the time‐mean eddy heat transport constitutes a considerable portion of the total time‐mean heat transport, in particular, in the tropics, in the Southern Ocean and in the Kuroshio Current. This research demonstrates that the variability of the eddy heat transport is a significant contributor to the variability of the total heat transport and globally it explains about 1/3 of its variance. Eddies are also found to explain a significant portion of the seasonal‐interannual heat transport variance.
The cell is a multi-scale structure with modular organization across at least four orders of magnitude
. Two central approaches for mapping this structure-protein fluorescent imaging and protein ...biophysical association-each generate extensive datasets, but of distinct qualities and resolutions that are typically treated separately
. Here we integrate immunofluorescence images in the Human Protein Atlas
with affinity purifications in BioPlex
to create a unified hierarchical map of human cell architecture. Integration is achieved by configuring each approach as a general measure of protein distance, then calibrating the two measures using machine learning. The map, known as the multi-scale integrated cell (MuSIC 1.0), resolves 69 subcellular systems, of which approximately half are to our knowledge undocumented. Accordingly, we perform 134 additional affinity purifications and validate subunit associations for the majority of systems. The map reveals a pre-ribosomal RNA processing assembly and accessory factors, which we show govern rRNA maturation, and functional roles for SRRM1 and FAM120C in chromatin and RPS3A in splicing. By integration across scales, MuSIC increases the resolution of imaging while giving protein interactions a spatial dimension, paving the way to incorporate diverse types of data in proteome-wide cell maps.
Summary
Background
ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T ...helper (Th)1, Th2 and Th17/Th22 pathways.
Objectives
The objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate‐to‐severe AD.
Methods A total of 36 patients with moderate‐to‐severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28‑day period (20 mg, 40 mg and 80 mg once daily).
Results
ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg −1·3 ± 2·1, P = 0·81; 40 mg −3·1 ± 2·7, P = 0·27; 80 mg −4·7 ± 2·1, P = 0·01; placebo −1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose‐dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis‐associated biomarker E selectin/SELE.
Conclusions
In patients with moderate‐to‐severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.
What's already known about this topic?
Currently available therapeutic options for atopic dermatitis (AD) include topical corticosteroids, calcineurin inhibitors, crisaborole, dupilumab, ciclosporin and phototherapy. However, few oral treatments are available and those are associated with safety concerns.
What does this study add?
ASN002, an oral, dual Janus kinase and spleen tyrosine kinase inhibitor, was well tolerated and showed promising efficacy and rapid onset of action in patients with moderate‐to‐severe AD at daily doses of 40 mg and 80 mg.
The encouraging efficacy, safety and tolerability profile of ASN002 warrant further investigation of ASN002 in patients with moderate‐to‐severe AD.
Linked Comment: Lebwohl. Br J Dermatol 2019; 181:658.
Plain language summary available online
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Remote and local forcing led to unprecedented drop and quick recovery in the South Indian Ocean heat content.
Following the onset of the strong 2014–2016 El Niño, a decade-long increase of the ...basin-wide sea level and heat content in the subtropical southern Indian Ocean (SIO) in 2004–2013 ended with an unprecedented drop, which quickly recovered during the weak 2017–2018 La Niña. Here, we show that the 2014–2016 El Niño contributed to the observed cooling through an unusual combination of both the reduced heat advection from the Pacific (dominant in the eastern SIO) and the basin-wide cyclonic wind anomaly that led to shoaling of isotherms (dominant in the western SIO). The ensuing recovery was mainly forced by an anticyclonic wind anomaly associated with stronger trade winds that caused deepening of isotherms and upper-ocean warming, effectively suppressing the 2014–2016 cooling signal propagating from the eastern boundary. The results presented here highlight the complexity of the SIO heat content variability driven by remote and local forcing.
When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas ...(HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens. ShRNA knockdown of HIF-1α significantly reduced deferoxamine-mediated lytic reactivation. HIF-1α directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE) located at nt -83 through -76 relative to the transcription initiation site. HIF-1α did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1α induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK) and gingival epithelial (hGET) cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF-1α and Blimp-1α, another cellular factor implicated in lytic reactivation. HIF-1α activity also accumulated along with Blimp-1α during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1α plays central roles in both EBV's natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF-1α protein accumulation are good candidates for development of a lytic-induction therapy for treating some EBV-associated malignancies.
Chromosome segregation during mitosis is highly regulated to ensure production of genetically identical progeny. Recurrent mitotic errors cause chromosomal instability (CIN), a hallmark of tumors. ...The E6 and E7 oncoproteins of high-risk human papillomavirus (HPV), which causes cervical, anal, and head and neck cancers (HNC), cause mitotic defects consistent with CIN in models of anogenital cancers, but this has not been studied in the context of HNC. Here, we show that HPV16 induces a specific type of CIN in patient HNC tumors, patient-derived xenografts, and cell lines, which is due to defects in chromosome congression. These defects are specifically induced by the HPV16 oncogene E6 rather than E7. We show that HPV16 E6 expression causes degradation of the mitotic kinesin CENP-E, whose depletion produces chromosomes that are chronically misaligned near spindle poles (polar chromosomes) and fail to congress. Though the canonical oncogenic role of E6 is the degradation of the tumor suppressor p53, CENP-E degradation and polar chromosomes occur independently of p53. Instead, E6 directs CENP-E degradation in a proteasome-dependent manner via the E6-associated ubiquitin protein ligase E6AP/UBE3A. This study reveals a mechanism by which HPV induces CIN, which may impact HPV-mediated tumor initiation, progression, and therapeutic response.
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