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Objectives: A novel AFR– albumin-derived neutrophil to lymphocyte ratio (dNLR) score (ADS) were reported to associate with clinical outcome in various malignancies, However, the relation between the ADS score and outcomes in coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI) has not been investigated.Methods: Three thousand five hundred and sixty-one patients were divided into two groups according to ADS score: low group (ADS score

Summary: Relationships among productivity, leaf phenology, and seasonal variation in moisture and light availability are poorly understood for evergreen broadleaved tropical/subtropical forests, which contribute 25% of terrestrial productivity. On the one hand, as moisture availability declines, trees shed leaves to reduce transpiration and the risk of hydraulic failure. On the other hand, increases in light availability promote the replacement of senescent leaves to increase productivity. Here, we provide a comprehensive framework that relates the seasonality of climate, leaf abscission, and leaf productivity across the evergreen broadleaved tropical/subtropical forest biome. The seasonal correlation between rainfall and light availability varies from strongly negative to strongly positive across the tropics and maps onto the seasonal correlation between litterfall mass and productivity for 68 forests. Where rainfall and light covary positively, litterfall and productivity also covary positively and are always greater in the wetter sunnier season. Where rainfall and light covary negatively, litterfall and productivity are always greater in the drier and sunnier season if moisture supplies remain adequate; otherwise productivity is smaller in the drier sunnier season. This framework will improve the representation of tropical/subtropical forests in Earth system models and suggests how phenology and productivity will change as climate change alters the seasonality of cloud cover and rainfall across tropical/subtropical forests. Public summary: • Three climate-phenology regimes are identified across tropical and subtropical forest biomes • Where light and water limit plant in dry season, litterfall and productivity peak in sunny wet season • Where light or water alternately limits plant, productivity peaks in wet season with low litterfall • Where water does not limit plant, litterfall and productivity peak in sunny dry season

It has been long established that the terrestrial vegetation in spring has stronger photosynthetic capability than in autumn. However, this study challenges this consensus by comparing photosynthetic capability of terrestrial vegetation between the spring and autumn seasons based on measurements of 100 in situ eddy covariance towers over global extratropical ecosystems. At the majority of these sites, photosynthetic capability, indicated by light use efficiency (LUE) and apparent quantum efficiency, is significantly higher in autumn than in spring, due to lower atmosphere vapor pressure deficit (VPD) at the same air temperature. Seasonal VPD differences also substantially explain the interannual variability of the differences in photosynthetic capability between spring and autumn. We further reveal that VPD in autumn is significantly lower than in spring over 74.14% of extratropical areas, based on a global climate dataset. In contrast, LUE derived from a data-driven vegetation production dataset is significantly higher in autumn in over 61.02% of extratropical vegetated areas. Six Earth system models consistently projected continuous larger VPD values in spring compared with autumn, which implies that the impacts on vegetation growth will long exist and should be adequately considered when assessing the seasonal responses of terrestrial ecosystems to future climate conditions. Public summary: • Autumn VPD is lower than spring VPD at the same air temperature over majority of the extratropical vegetated land • Photosynthetic capability is significantly higher in autumn than in spring due to lower VPD • Earth System Models projected continuous larger VPD values in spring as against autumn

Myocardial supply changes to accommodate the variation of myocardial demand across the heart wall to maintain normal cardiac function. A computational framework that couples the systemic circulation of a left ventricular (LV) finite element model and coronary perfusion in a closed loop is developed to investigate the transmural distribution of the myocardial demand (work density) and supply (perfusion) ratio. Calibrated and validated against measurements of LV mechanics and coronary perfusion, the model is applied to investigate changes in the transmural distribution of passive coronary perfusion, myocardial work density, and their ratio in response to changes in LV contractility, preload, afterload, wall thickness, and cavity volume. The model predicts the following: (1) Total passive coronary flow varies from a minimum value at the endocardium to a maximum value at the epicardium transmurally that is consistent with the transmural distribution of IMP; (2) Total passive coronary flow at different transmural locations is increased with an increase in either contractility, afterload, or preload of the LV, whereas is reduced with an increase in wall thickness or cavity volume; (3) Myocardial work density at different transmural locations is increased transmurally with an increase in either contractility, afterload, preload or cavity volume of the LV, but is reduced with an increase in wall thickness; (4) Myocardial work density-perfusion mismatch ratio at different transmural locations is increased with an increase in contractility, preload, wall thickness or cavity volume of the LV, and the ratio is higher at the endocardium than the epicardium. These results suggest that an increase in either contractility, preload, wall thickness, or cavity volume of the LV can increase the vulnerability of the subendocardial region to ischemia.

Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic disease manifested in hepatic steatosis, inflammation, fibrosis, etc., which affects over one-quarter of the population around the world. Since no effective therapeutic drugs are available to cope with this widespread epidemic, the functional research of genes with altered expression during NAFLD helps understand the pathogenesis of this disease and the development of new potential therapeutic targets for drugs. In the current work, we discovered via the analysis of the Gene Expression Omnibus (GEO) dataset that cysteine sulfinic acid decarboxylase (CSAD) decreased significantly in NAFLD patients, which was also confirmed in multiple NAFLD mouse models (HFD-fed C57BL/6J, db/db and HFHFrHC-fed C57BL/6J mice). Next, CSAD’s function in the progression of NAFLD was explored using AAV-mediated liver-directed gene overexpression in an HFD-fed mouse model, where the overexpression of CSAD in the liver could alleviate NAFLD-associated pathologies, including body weight, liver/body weight ratio, hepatic triglyceride and total cholesterol, and the degree of steatosis. Mechanically, we found that the overexpression of CSAD could increase the expression of some genes related to fatty acid β-oxidation (Acad1, Ppara, and Acox1). Furthermore, we also detected that CSAD could improve mitochondrial injury in vitro and in vivo. Finally, we proposed that the effect of CSAD on lipid accumulation might be independent of the taurine pathway. In conclusion, we demonstrated that CSAD is involved in the development of NAFLD as a protective factor, which suggested that CSAD has the potential to become a new target for drug discovery in NAFLD.

In the context of carbon neutrality, the development of new digital infrastructure (NDI) and the improvement of digital capabilities are essential, in order to speed up the transformation of the energy structure. Based on the balanced panel data of 30 provinces in China from 2008 to 2019, we empirically analyzed the impact of NDI on the structural transformation of energy in China and its mechanisms of action. The results demonstrated that (1) NDI had a positive impact on China’s energy transition, and the empirical results were robust. (2) The mediating effect showed that NDI had a positive impact on the transformation of energy structure, through improving green total factor productivity and green finance. (3) The heterogeneity analysis indicated that NDI made a more significant contribution to the transformation of the energy structure in regions with lower pollution levels and in those with energy cooperation policies. This study provides a policy reference for Chinese energy transition from the perspective of the digital economy.

The placenta contains multiple biologically active substances, which exert antioxidation, anti-inflammatory, immunomodulatory, and delayed aging effects. Its extract can improve hepatic morphology and function: on the one hand, it can reduce liver interstitial collagen deposition, lipogenesis, and inflammatory cell infiltration and improve fibrosis; on the other hand, it can prevent hepatocellular degeneration by scavenging reactive oxygen species (ROS) and inhibiting inflammatory cytokine production, further improve hepatocyte apoptosis and necrosis, and promote hepatocyte regeneration, making it a promising liver-protective agent. Current research on placenta extract (PE) mainly focuses on treating a specific type of liver injury, and there are no systematic reports. Therefore, this review comprehensively summarizes the treatment reports of PE on liver injury and analyzes its mechanism of action.

Placental extract has been used for skin care and delaying skin aging. Cow placenta is an abundant resource with a large mass, which has not been harnessed effectively. Cow placenta extract (CPE) has the functions of antioxidation, anti-inflammatory, promoting growth and development, and promoting hair growth. However, little is known about the effect of oral administration of cow placenta extract on skin conditions. Therefore, the present study aimed to investigate the antioxidant capacity of CPE in vitro and in vivo and its protective effect on d-galactose (D-gal) induced skin aging in mice. The results showed that CPE had strong free radical scavenging, reducing and metal chelating activities. CPE can increase the activity of catalase (CAT), glutathione peroxidase (GSH-Px), peroxidase (POD), superoxide dismutase (SOD), and the content of glutathione (GSH), decrease the content of malondialdehyde (MDA). Moreover, CPE can decrease the gene and protein expression of matrix metalloproteinase 1a (MMP-1a) and matrix metalloproteinase 3 (MMP-3) and increase the expression of transforming growth factor-β (TGF-β) and tissue inhibitor of metalloproteinase 1 (TIMP-1) of mouse skin. Histopathological analysis showed CPE reduced the collagen damage caused by D-gal, increased collagen synthesis and reduced its degradation to delay skin aging.

The 11q deletion (del(11q)) is a conventional cytogenetic aberration observed in chronic lymphocytic leukemia (CLL) patients. However, the prevalence and the prognostic value of del(11q) are still controversial. In this research, we retrospectively explored the prevalence, association, and prognostic significance of del(11q) in 352 untreated and 99 relapsed/refractory Chinese CLL patients. Totally 11.4% of untreated and 19.2% of relapsed/refractory patients harbored del(11q). Del(11q) was more common in patients with β2-microglobulin > 3.5 mg/L, positive CD38, positive zeta-chain associated protein kinase 70, unmutated immunoglobulin heavy variable-region gene and ataxia telangiectasia mutated mutation. Kaplan-Meier method and univariate Cox regression indicated that del(11q) was an independent prognostic factor for overall survival (OS). Based on the results of univariate Cox regression analysis, two nomograms that included del(11q) were established to predict survival. Desirable area under curve of receiver operating characteristic curves was obtained in the training and validation cohorts. In addition, the calibration curves for the probability of survival showed good agreement between the prediction by nomogram and actual observation. In summary, the prevalence of del(11q) is relatively low in our cohort and del(11q) is an unfavorable prognostic factor for untreated CLL patients. Besides, these two nomograms could be used to accurately predict the prognosis of untreated CLL patients.

As an important mechanical cue in the extracellular microenvironment, osmotic stress directly affects the proliferation, migration, and differentiation of cells. In this paper, we focused on the influence of hypertonic pressure on the colony morphology, stemness, and self-renew of mouse embryonic stem cells (mESCs). Our results showed that culture media with hypertonic pressure are more conducive to the maintenance of 3D colony morphology and pluripotency of mESCs after withdrawing the glycogen synthase kinase 3β (GSK3β) inhibitor CHIR99021 and the mitogen-activated protein kinase (MEK) inhibitor PD0325901 (hereinafter referred to as 2i) for 48 h. Furthermore, we revealed the microscopic mechanisms of the this finding: hypertonic pressure resulted in the depolymerization of F-actin cytoskeleton and limits Yes-associated protein (hereinafter referred to as YAP) transmission into the nucleus which play a vital role in the regulation of cell proliferation, and resulting in cell-cycle arrest at last.

Background: The tumor microenvironment (TME) mainly comprises tumor cells and tumor-infiltrating immune cells mixed with stromal components. Latestresearch hasdisplayed that tumor immune cell infiltration (ICI) is associated with the clinical outcome of patients with osteosarcoma (OS). This work aimed to build a gene signature according to ICI in OS for predicting patient outcomes.Methods: The TARGET-OS dataset was used for model training, while the GSE21257 dataset was taken forvalidation. Unsupervised clustering was performed on the training cohort based on the ICI profiles. The Kaplan–Meier estimator and univariate Cox proportional hazards models were used to identify the differentially expressed genes between clusters to preliminarily screen for potential prognostic genes. We incorporated these potential prognostic genes into a LASSO regression analysis and produced a gene signature, which was next assessed with the Kaplan–Meier estimator, Cox proportional hazards models, ROC curves, IAUC, and IBS in the training and validation cohorts. In addition, we compared our signature to previous models. GSEAswere deployed to further study the functional mechanism of the signature. We conducted an analysis of 22 TICsfor identifying the role of TICs in the gene signature’s prognosis ability.Results: Data from the training cohort were used to generate a nine-gene signature. The Kaplan–Meier estimator, Cox proportional hazards models, ROC curves, IAUC, and IBS validated the signature’s capacity and independence in predicting the outcomes of OS patients in the validation cohort. A comparison with previous studies confirmed the superiority of our signature regarding its prognostic ability. Annotation analysis revealed the mechanism related to the gene signature specifically. The immune-infiltration analysis uncoveredkey roles for activated mast cells in the prognosis of OS.Conclusion: We identified a robust nine-gene signature (ZFP90, UHRF2, SELPLG, PLD3, PLCB4, IFNGR1, DLEU2, ATP6V1E1, and ANXA5) that can predict OS outcome precisely and is strongly linked to activated mast cells.

Aims: The present study aimed to investigate the prognostic role of derived neutrophil-to-lymphocyte ratio (dNLR) in patients with coronary heart disease (CHD) after PCI.Methods: A total of 3,561 post-PCI patients with CHD were retrospectively enrolled in the CORFCHD-ZZ study from January 2013 to December 2017. The patients (3,462) were divided into three groups according to dNLR tertiles: the first tertile (dNLR < 1.36; n = 1,139), second tertile (1.36 ≥ dNLR < 1.96; n = 1,166), and third tertile(dNLR ≥ 1.96; n = 1,157). The mean follow-up time was 37.59 ± 22.24 months. The primary endpoint was defined as mortality (including all-cause death and cardiac death), and the secondary endpoint was major adverse cardiovascular events (MACEs) and major adverse cardiovascular and cerebrovascular events (MACCEs).Results: There were 2,644 patients with acute coronary syndrome (ACS) and 838 patients with chronic coronary syndrome (CCS) in the present study. In the total population, the all-cause mortality (ACM) and cardiac mortality (CM) incidence was significantly higher in the third tertile than in the first tertile [hazard risk (HR) = 1.8 (95% CI: 1.2–2.8), p = 0.006 and HR = 2.1 (95% CI: 1.23–3.8), p = 0.009, respectively]. Multivariate Cox regression analyses suggested that compared with the patients in the first tertile than those in the third tertile, the risk of ACM was increased 1.763 times (HR = 1.763, 95% CI: 1.133–2.743, p = 0.012), and the risk of CM was increased 1.763 times (HR = 1.961, 95% CI: 1.083–3.550, p = 0.026) in the higher dNLR group during the long-term follow-up. In both ACS patients and CCS patients, there were significant differences among the three groups in the incidence of ACM in univariate analysis. We also found that the incidence of CM was significantly different among the three groups in CCS patients in both univariate analysis (HR = 3.541, 95% CI: 1.154–10.863, p = 0.027) and multivariate analysis (HR = 3.136, 95% CI: 1.015–9.690, p = 0.047).Conclusion: The present study suggested that dNLR is an independent and novel predictor of mortality in CHD patients who underwent PCI.

Objective: The U-shaped association between serum uric acid (SUA) and the functional outcome has been found in acute ischemic stroke (AIS). However, it is unclear if SUA is associated with red blood cell morphology in AIS. This study aimed to determine the relationship between SUA and red blood cell distribution width (RDW) in patients with AIS.Methods: A cross-sectional study including 438 consecutive patients with AIS was conducted. SUA and RDW, biochemical parameters that reflect the heterogeneity of red blood cell volume, were evaluated on admission. We evaluated the association between SUA and RDW through linear curve fitting analyses and two-piecewise regression analyses.Results: The association between SUA levels and RDW followed a U-shape in all patients. In females, the values of RDW significantly decreased with the increment of SUA (per mg/dl: β, −1.45; 95% CI: −2.15 to −0.75; p < 0.001) in patients with SUA

BackgroundThere is a significant survival difference and lack of effective treatment among breast cancer patients with liver metastasis. This present study aimed to construct a novel prognostic score for predicting the prognosis and locoregional treatment benefit of de novo metastatic breast cancer with liver metastasis (BCLM).MethodsIn total, 2,398 eligible patients between 2010 and 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. They were assigned to the training set including 1,662 patients (2010–2014) and validation set comprising 736 patients (2015–2016) depending on the time of diagnosis. The prognostic score was based on regression coefficients in the multivariate Cox regression analysis. And then, patients were stratified into low-, intermediate-, and high-risk groups by the prognostic score. The discrimination and calibration of prognostic score were evaluated using time-dependent receiver operating characteristic (ROC) curves analysis and calibration curves, respectively. Subgroup analysis was performed to evaluate locoregional surgery and chemotherapy benefit in different risk groups.ResultsAge, race, insurance and marital status, T stage, pathological grade, molecular subtypes, and extrahepatic metastasis were identified as independent prognostic variables in the prognostic score. The prognostic score showed high discrimination power with an area under the curve (AUC) of 0.77 and 0.72 and excellent agreement suggested by calibration plots in the training and validation sets, respectively. Intermediate-risk [hazard ratio (HR) 2.39, 95% confidence interval (CI) 2.09–2.73, P

The El Niño Southe58rn Oscillation (ENSO) is a typical oscillation affecting climate change, and its stable periodicity, long-lasting effect, and predictable characteristics have become important indicators for regional climate prediction. In this study, we analyze the Standardized Precipitation Evapotranspiration Index (SPEI), the Niño3.4 index, the Southern Oscillation Index (SOI), and the Multivariate ENSO Index (MEI). Additionally, we explore the spatial and temporal distribution of the correlation coefficients between ENSO and SPEI and the time lag between ENSO events of varying intensities and droughts. The results reveal that the use of Nino3.4, MEI, and SOI produces differences in the occurrence time, end time, and intensity of ENSO events. Nino3.4 and MEI produce similar results for identifying ENSO events, and the Nino3.4 index accurately identifies and describes ENSO events with higher reliability. In China, the drought-sensitive areas vulnerable to ENSO events include southern China, the Jiangnan region, the middle and lower reaches of the Yangtze River, and the arid and semi-arid areas of northwestern China. Droughts in these areas correlate significantly with meteorological drought, and time-series correlations between ENSO events and droughts are significantly stronger in regions close to the ocean. Drought occurrence lags ENSO events: when using the Niño3.4 index to identify ENSO, droughts lag the strongest and weakest El Niño events by 0–12 months. However, when using the MEI as a criterion for ENSO, droughts lag the strongest and weakest El Niño events by 0–7 months. The time lag between the strongest ENSO event and drought is shorter than that for the weakest ENSO event, and droughts have a wider impact. The results of this study can provide a climate-change-compatible basis for drought monitoring and prediction.

Vegetation optical depth (VOD), as a microwave-based estimate of vegetation water and biomass content, is increasingly used to study the impact of global climate and environmental changes on vegetation. However, current global operational VOD products have a coarse spatial resolution (~25 km), which limits their use for agriculture management and vegetation dynamics monitoring at regional scales (1–5 km). This study aims to retrieve high-resolution VOD from the C-band Sentinel-1 backscatter data over a grassland of the Heihe River Basin in northwestern China. The proposed approach used an analytical solution of a simplified Water Cloud Model (WCM), constrained by given soil moisture estimates, to invert VOD over grassland with 1 km spatial resolution during the 2018–2020 period. Our results showed that the VOD estimates exhibited large spatial variability and strong seasonal variations. Furthermore, the dynamics of VOD estimates agreed well with optical vegetation indices, i.e., the mean temporal correlations with normalized difference vegetation index (NDVI), enhanced vegetation index (EVI), and leaf area index (LAI) were 0.76, 0.75, and 0.75, respectively, suggesting that the VOD retrievals could precisely capture the dynamics of grassland.

Computer vision technology is increasingly being used in areas such as intelligent security and autonomous driving. Users need accurate and reliable visual information, but the images obtained under severe weather conditions are often disturbed by rainy weather, causing image scenes to look blurry. Many current single image deraining algorithms achieve good performance but have limitations in retaining detailed image information. In this paper, we design a Scale-space Feature Recalibration Network (SFR-Net) for single image deraining. The proposed network improves the image feature extraction and characterization capability of a Multi-scale Extraction Recalibration Block (MERB) using dilated convolution with different convolution kernel sizes, which results in rich multi-scale rain streaks features. In addition, we develop a Subspace Coordinated Attention Mechanism (SCAM) and embed it into MERB, which combines coordinated attention recalibration and a subspace attention mechanism to recalibrate the rain streaks feature information learned from the feature extraction phase and eliminate redundant feature information to enhance the transfer of important feature information. Meanwhile, the overall SFR-Net structure uses dense connection and cross-layer feature fusion to repeatedly utilize the feature maps, thus enhancing the understanding of the network and avoiding gradient disappearance. Through extensive experiments on synthetic and real datasets, the proposed method outperforms the recent state-of-the-art deraining algorithms in terms of both the rain removal effect and the preservation of image detail information.

Background: The outbreak of severe respiratory syndrome coronavirus 2 (SARS-COV-2) has led to long periods of social isolation for individuals across the world. Although medical students generally have a high prevalence of mental health problems, they have received less attention than other groups concerning the impact of SARS-COV-2. Therefore, the present study investigated the mental health status, risk factors, and protective factors for mental health problems in medical students in North China during the SARS-COV-2 pandemic.Methods: A WeChat-based survey, which included the Depression Anxiety Stress Scale-21 and measures of social demographics, was performed twice. Risk and protective factors were identified by binary logistic regression analysis.Results: A total of 702 effective questionnaires were collected in two separate surveys. In total, 24.55% of medical students were suffering anxiety to different degrees of severity, 13.18% were suffering depression in the first survey, and 3.71% wanted to give up working in primary medical care during the SARS-COV-2 pandemic in the second survey. In contrast, during the SARS-COV-2 pandemic, a risk factor for anxiety and depression was gender which is male, while being knowledgeable about the SARS-COV-2 pandemic and having a lower academic burden were both protective factors.Conclusions: Measures are required to prevent increases in mental health problems in medical students. Our findings suggest that increasing knowledge about the SARS-COV-2 pandemic and reducing academic burden in medical students is extremely important during the SARS-COV-2 pandemic.

Background: De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: It is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1–3N+ or pT2–3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P. Findings: Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45–57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79–1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75–1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar. Interpretation: Both TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects. Funding: This work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).