Increasing temperature trends are expected to impact yields of major field crops by affecting various plant processes, such as phenology, growth, and evapotranspiration. However, future projections ...typically do not consider the effects of agronomic adaptation in farming practices. We use an ensemble of seven Global Gridded Crop Models to quantify the impacts and adaptation potential of field crops under increasing temperature up to 6 K, accounting for model uncertainty. We find that without adaptation, the dominant effect of temperature increase is to shorten the growing period and to reduce grain yields and production. We then test the potential of two agronomic measures to combat warming-induced yield reduction: (i) use of cultivars with adjusted phenology to regain the reference growing period duration and (ii) conversion of rainfed systems to irrigated ones in order to alleviate the negative temperature effects that are mediated by crop evapotranspiration. We find that cultivar adaptation can fully compensate global production losses up to 2 K of temperature increase, with larger potentials in continental and temperate regions. Irrigation could also compensate production losses, but its potential is highest in arid regions, where irrigation expansion would be constrained by water scarcity. Moreover, we discuss that irrigation is not a true adaptation measure but rather an intensification strategy, as it equally increases production under any temperature level. In the tropics, even when introducing both adapted cultivars and irrigation, crop production declines already at moderate warming, making adaptation particularly challenging in these areas.
In breast cancers, only a minority of patients fully benefit from the different chemotherapy regimens currently in use. Identification of markers that could predict the response to a particular ...regimen would thus be critically important for patient care. In cell lines or animal models, tumor protein p53 (TP53) plays a critical role in modulating the response to genotoxic drugs. TP53 is activated in response to DNA damage and triggers either apoptosis or cell-cycle arrest, which have opposite effects on cell fate. Yet, studies linking TP53 status and chemotherapy response have so far failed to unambiguously establish this paradigm in patients. Breast cancers with a TP53 mutation were repeatedly shown to have a poor outcome, but whether this reflects poor response to treatment or greater intrinsic aggressiveness of the tumor is unknown.
In this study we analyzed 80 noninflammatory breast cancers treated by frontline (neoadjuvant) chemotherapy. Tumor diagnoses were performed on pretreatment biopsies, and the patients then received six cycles of a dose-dense regimen of 75 mg/m(2) epirubicin and 1,200 mg/m(2) cyclophosphamide, given every 14 days. After completion of chemotherapy, all patients underwent mastectomies, thus allowing for a reliable assessment of chemotherapy response. The pretreatment biopsy samples were used to determine the TP53 status through a highly efficient yeast functional assay and to perform RNA profiling. All 15 complete responses occurred among the 28 TP53-mutant tumors. Furthermore, among the TP53-mutant tumors, nine out of ten of the highly aggressive basal subtypes (defined by basal cytokeratin KRT immunohistochemical staining) experienced complete pathological responses, and only TP53 status and basal subtype were independent predictors of a complete response. Expression analysis identified many mutant TP53-associated genes, including CDC20, TTK, CDKN2A, and the stem cell gene PROM1, but failed to identify a transcriptional profile associated with complete responses among TP53 mutant tumors. In patients with unresponsive tumors, mutant TP53 status predicted significantly shorter overall survival. The 15 patients with responsive TP53-mutant tumors, however, had a favorable outcome, suggesting that this chemotherapy regimen can overcome the poor prognosis generally associated with mutant TP53 status.
This study demonstrates that, in noninflammatory breast cancers, TP53 status is a key predictive factor for response to this dose-dense epirubicin-cyclophosphamide regimen and further suggests that the basal subtype is exquisitely sensitive to this association. Given the well-established predictive value of complete responses for long-term survival and the poor prognosis of basal and TP53-mutant tumors treated with other regimens, this chemotherapy could be particularly suited for breast cancer patients with a mutant TP53, particularly those with basal features.
Protein subcellular localization has been systematically characterized in budding yeast using fluorescently tagged proteins. Based on the fluorescence microscopy images, subcellular localization of ...many proteins can be classified automatically using supervised machine learning approaches that have been trained to recognize predefined image classes based on statistical features. Here, we present an unsupervised analysis of protein expression patterns in a set of high-resolution, high-throughput microscope images. Our analysis is based on 7 biologically interpretable features which are evaluated on automatically identified cells, and whose cell-stage dependency is captured by a continuous model for cell growth. We show that it is possible to identify most previously identified localization patterns in a cluster analysis based on these features and that similarities between the inferred expression patterns contain more information about protein function than can be explained by a previous manual categorization of subcellular localization. Furthermore, the inferred cell-stage associated to each fluorescence measurement allows us to visualize large groups of proteins entering the bud at specific stages of bud growth. These correspond to proteins localized to organelles, revealing that the organelles must be entering the bud in a stereotypical order. We also identify and organize a smaller group of proteins that show subtle differences in the way they move around the bud during growth. Our results suggest that biologically interpretable features based on explicit models of cell morphology will yield unprecedented power for pattern discovery in high-resolution, high-throughput microscopy images.
Improving the model-based predictions of plant species under a projected climate is essential to better conserve our biodiversity. However, the mechanistic link between climatic variation and plant ...response at the species level remains relatively poorly understood and not accurately developed in Dynamic Vegetation Models (DVMs). We investigated the acclimation to climate of Cedrus atlantica (Atlas cedar), an endemic endangered species from northwestern African mountains, in order to improve the ability of a DVM to simulate tree growth under climatic gradients. Our results showed that the specific leaf area, leaf C:N and sapwood C:N vary across the range of the species in relation to climate. Using the model parameterized with the three traits varying with climate could improve the simulated local net primary productivity (NPP) when compared to the model parameterized with fixed traits. Quantifying the influence of climate on traits and including these variations in DVMs could help to better anticipate the consequences of climate change on species dynamics and distributions. Additionally, the simulation with computed traits showed dramatic drops in NPP over the course of the 21st century. This finding is in line with other studies suggesting the decline in the species in the Rif Mountains, owing to increasing water stress.
Many mutations confer one or more toxic function(s) on copper/zinc superoxide dismutase 1 (SOD1) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a ...conformation-specific antibody that detects misfolded SOD1 (C4F6), we found that oxidized wild-type SOD1 and mutant SOD1 share a conformational epitope that is not present in normal wild-type SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord were markedly C4F6 immunoreactive, indicating that an aberrant wild-type SOD1 species was present. Recombinant, oxidized wild-type SOD1 and wild-type SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal transport in a manner similar to that of FALS-linked mutant SOD1. Our findings suggest that wild-type SOD1 can be pathogenic in SALS and identify an SOD1-dependent pathogenic mechanism common to FALS and SALS.
In this study, we aimed to determine the frequency and clinical impact of new ischemic lesions detected with diffusion-weighted-imaging-MRI (DWI-MRI) as well as the clinical outcomes after carotid ...artery stenting (CAS) using the simple flow blockage technique (SFB). This is a retrospective study with data extraction from a monocentric prospective clinical registry (from 2017 to 2019) of consecutive patients admitted for symptomatic cervical ICA stenosis or web. Herein, patients benefited from DWI-MRI before and within 48 h of CAS for symptomatic ICA stenosis or web. The primary endpoint was the frequency of new DWI-MRI ischemic lesions and the secondary (composite) endpoint was the rate of mortality, symptomatic stroke or acute coronary syndrome within 30 days of the procedure. All of the 82 CAS procedures were successfully performed. Among the 33 patients (40.2%) with new DWI-MRI ischemic lesions, 30 patients were asymptomatic (90.9%). Irregular carotid plaque surface with (n = 13, 44.8%) or without ulceration (n = 12, 60.0%) was associated with higher rates of new DWI-MRI lesions by comparison to patients with a regular plaque (n = 7, 25%) (p = 0.048) using the univariate analysis. Less than half of this CAS cohort using the SFB technique had new ischemic lesions detected with DWI-MRI. Among these patients, more than 90% were asymptomatic. Irregularity of the plaque seems to increase the risk of peri-procedural DWI-MRI lesions.
Statistical emulation allows combining advantageous features of statistical and process-based crop models for understanding the effects of future climate changes on crop yields. We describe here the ...development of emulators for nine process-based crop models and five crops using output from the Global Gridded Model Intercomparison Project (GGCMI) Phase 2. The GGCMI Phase 2 experiment is designed with the explicit goal of producing a structured training dataset for emulator development that samples across four dimensions relevant to crop yields: atmospheric carbon dioxide (CO2) concentrations, temperature, water supply, and nitrogen inputs (CTWN). Simulations are run under two different adaptation assumptions: that growing seasons shorten in warmer climates, and that cultivar choice allows growing seasons to remain fixed. The dataset allows emulating the climatological-mean yield response of all models with a simple polynomial in mean growing-season values. Climatological-mean yields are a central metric in climate change impact analysis; we show here that they can be captured without relying on interannual variations. In general, emulation errors are negligible relative to differences across crop models or even across climate model scenarios; errors become significant only in some marginal lands where crops are not currently grown. We demonstrate that the resulting GGCMI emulators can reproduce yields under realistic future climate simulations, even though the GGCMI Phase 2 dataset is constructed with uniform CTWN offsets, suggesting that the effects of changes in temperature and precipitation distributions are small relative to those of changing means. The resulting emulators therefore capture relevant crop model responses in a lightweight, computationally tractable form, providing a tool that can facilitate model comparison, diagnosis of interacting factors affecting yields, and integrated assessment of climate impacts.
Learning Objectives
After completing this course, the reader will be able to:
Analyze the role of p53 mutation in ER‐negative tumors in conferring increased sensitivity to high‐dose alkylating ...agents, in order to treat patients with this phenotype using regimens containing high‐dose alkylating agents.
Evaluate the role played by dysfunctional p53 in conferring chemosensitivity to anthracyclines, and explore the possibility of using high‐dose alkylating agents to overcome the resistance of ER+/p53 mutated tumors.
Examine the mechanism for determining p53 gene function (functional analysis of separated alleles in yeast as opposed to immunohistochemistry) to more precisely determine the role of p53 activation in specific tumors, in order to select appropriate patients for treatment with high‐dose alkylating agents.
This article is available for continuing medical education credit at CME.TheOncologist.com
The predictive value of p53 for the efficacy of front‐line anthracycline‐based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II–III breast cancer patients treated front line with anthracycline‐based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)− tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose‐dense anthracycline–cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high‐dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER− tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose‐intense alkylating regimen. The latter allowed very high levels of pCR in triple‐negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER− p53‐mutated breast cancer patients could significantly improve their response.
The study examines three series of de novo stage II–III breast cancer patients treated front line with anthracycline‐based regimens of various cyclophosphamide dose intensities. The results strongly suggest that cyclophosphamide dose intensification in estrogen receptor–negative p53‐mutated breast cancer patients could significantly improve their response.
BackgroundThe obstructive sleep apnoea syndrome (OSAS) results from a combination of structural and neuromotor factors; however, the relative contributions of these factors have not been studied ...during the important developmental phase of adolescence. We hypothesised that adenotonsillar volume (ATV), nasopharyngeal airway volume (NPAV), upper airway critical closing pressure (Pcrit) in the hypotonic and activated neuromotor states, upper airway electromyographic response to subatmospheric pressure and the ventilatory response to CO2 during sleep would be major predictors of OSAS risk.Methods42 obese adolescents with OSAS and 37 weight-matched controls underwent upper airway MRI, measurements of Pcrit, genioglossal electromyography and ventilatory response to CO2 during wakefulness and sleep.ResultsATV, NPAV, activated and hypotonic Pcrit, genioglossal electromyography and ventilatory response to CO2 during sleep were all associated with OSAS risk. Multivariate models adjusted for age, gender, body mass index and race indicated that ATV, NPAV and activated Pcrit each independently affected apnoea risk in adolescents; genioglossal electromyography was independently associated in a reduced sample. There was significant interaction between NPAV and activated Pcrit (p=0.021), with activated Pcrit more strongly associated with OSAS in adolescents with larger NPAVs and NPAV more strongly associated with OSAS in adolescents with more negative activated closing pressure.ConclusionsOSAS in adolescents is mediated by a combination of anatomic (ATV, NPAV) and neuromotor factors (activated Pcrit). This may have important implications for the management of OSAS in adolescents.
Enhanced and aberrant angiogenesis is one of the main features of Moyamoya disease (MMD) pathogenesis. The ring finger protein 213 (RNF213) and the variant p.R4810K have been linked with higher risks ...of MMD and intracranial arterial occlusion development in east Asian populations. The role of RNF213 in diverse aspects of the angiogenic process, such as proliferation, migration and capillary-like formation, is well-known but has been difficult to model in vitro. To evaluate the effect of the
MMD-associated gene on the angiogenic activity, we have generated RNF213 knockout in human cerebral microvascular endothelial cells (hCMEC/D3-RNF213
) using the CRISPR-Cas9 system. Matrigel-based assay and a tri-dimensional (3D) vascularized model using the self-assembly approach of tissue engineering were used to assess the formation of capillary-like structures. Quite interestingly, this innovative in vitro model of MMD recapitulated, for the first time, disease-associated pathophysiological features such as significant increase in angiogenesis in confluent endothelial cells devoid of RNF213 expression. These cells, grown to confluence, also showed a pro-angiogenic signature, i.e., increased secretion of soluble pro-angiogenic factors, that could be eventually used as biomarkers. Interestingly, we demonstrated that that these MMD-associated phenotypes are dependent of the cellular state, as only noted in confluent cells and not in proliferative RNF213-deficient cells.
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