Generating spatiotemporally continuous land surface temperature (LST) data is in great demand for hydrology, meteorology, ecology, environmental studies, etc. However, the thermal infrared ...(TIR)-based LST measurements are prone to cloud contamination with missing pixels. To repair the missing pixels, a new XGBoost-based linking approach for reconstructing daytime and nighttime Moderate Resolution Imaging Spectroradiometer (MODIS) LST measurements was introduced. The instantaneous solar radiation and two soil-related predictors from China Data Assimilation System (CLDAS) 0.0625°/1-h data were selected as the linking variables to depict the relationship with instantaneous MODIS LST data. Other land surface properties, including two vegetation indices, the water index, the surface albedo, and topographic parameters, were also used as the predictor variables. The XGBoost method was used to fit an LST linking model by the training datasets from clear-sky pixels and was then applied to the MODIS Aqua-Terra LSTs during summer time (June to August) in 2017 and 2018 across China. The recovered LST data was further rectified with the Savitzky–Golay (SG) filtering method. The results showed the distribution of the reconstructed LSTs present a reasonable pattern for different land-cover types and topography. The evaluation results using in situ longwave radiation measurements showed the RMSE varies from 3.91 K to 5.53 K for the cloud-free pixels and from 4.42 K to 4.97 K for the cloud-covered pixels. In addition, the reconstructed LST products correlated well with CLDAS LST data with similar LST spatial patterns. The variable importance analysis revealed that the two soil-related predictors and the elevation variable are key parameters due to their great contribution to the XGBoost model performance.
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Aberrant expression of miR-363-3p is seen in a wide array of cancers. The exact function of miR-363-3p in colorectal cancer (CRC), and the underlying mechanisms remain undefined. In ...the current study, we observed a down-regulation of miR-363-3p in CRC tissues, along with a strong correlation between low miR-363-3p levels and clinico-pathological parameters like tumor stage and lymph node metastasis. Ectopic overexpression of miR-363-3p in HT29 and HCT116 cell lines effectively inhibited cell proliferation and metastasis, and promoted apoptosis. Concurrently, miR-363-3p inhibition facilitated cell proliferation and suppressed apoptosis. Consistent with the in vitro findings, tumor growth and metastasis were also suppressed by the overexpression of miR-363-3p in vivo. Furthermore, miR-363-3p overexpression resulted in a significant decrease in SphK2 mRNA and protein levels, while miR-363-3p inhibition elevated SphK2 levels in CRC cell lines. Overexpression of SphK2 significantly abrogated the effects of miR-363-3p on cell growth, apoptosis, and metastasis. Taken together, our findings establish miR-363-3p as a potential tumor suppressor in CRC with SphK2 as its downstream target.
Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be ...susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET.
We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays.
The objective response rate was 72% (95% confidence interval CI, 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC.
In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the ...therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.
After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy.
Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.
The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
Background. Clear cell renal cell carcinoma (ccRCC) is a malignant tumor with high morbidity and mortality. As a member of the Nudix hydrolase superfamily, Nudix (nucleoside diphosphate-linked moiety ...X)-type motif 1 (NUDT1) is closely related to the occurrence and development of cancer. Our study aims to explore the role of NUDT1 in ccRCC and its relationship with immune infiltration. Methods. The NUDT1 expression matrix and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) database. The expression difference of NUDT1 in ccRCC and its relationship with the clinical characteristics were investigated using R software. Kaplan–Meier (K–M) analysis, univariate Cox regression, multivariate Cox regression, receiver operating characteristic (ROC) curve, and nomogram were utilized to evaluate the survival and prognosis of patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were utilized to explore the function of differential genes in low- or high-expression group of NUDT1. TCGA dataset and Tumor IMmune Estimation Resource (TIMER) database were utilized to explore the relationship between NUDT1 and immune infiltration. Finally, TCGA dataset was utilized for gene set enrichment analysis (GSEA). Results. NUDT1 was not only overexpressed in ccRCC but also significantly correlated with clinicopathological features (P<0.05). K–M survival analysis showed that upregulated NUDT1 was closely related to the decrease of overall survival (OS) and progression-free survival (PFS) in ccRCC patients. Multivariate Cox regression revealed that NUDT1 was a independent prognostic indicator (HR = 1.437, 95% CI: 1.065–1.939, P=0.018). The ROC curve showed that NUDT1 had a certain accuracy in predicting the outcome of ccRCC patiens. Furthermore, a total of 150 coexpressed genes and 1,886 differentially expressed genes (DEGs) were identified. GO/KEGG and GSEA results suggested that NUDT1 and its DEGs were involved in the immune-related pathways. NUDT1 expression was positively correlated with infiltrating levels of regulatory T cells (Tregs), CD8+ T cells, follicular helper T cells, and M0 macrophages. In addition, NUDT1 was positively related to immune checkpoints, such as PD-1, LAG3, CTLA4, and CD70, in ccRCC. Conclusion. NUDT1 plays a key role in the prognosis and immune cell infiltration of ccRCC patients, indicating its potential use as a prognostic biomarker and therapeutic target.
To determine tolerability, pharmacokinetics, and pharmacodynamics of PD-0325901, a highly potent, selective, oral mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase ...1/2 inhibitor in advanced cancer patients.
Sixty-six patients received PD-0325901 at doses from 1 mg once daily to 30 mg twice daily (BID). Cycles were 28 days; three administration schedules were evaluated. Pharmacokinetic parameters were assessed and tumor biopsies were done to evaluate pharmacodynamics.
Common adverse events were rash, diarrhea, fatigue, nausea, and visual disturbances including retinal vein occlusion (RVO; n = 3). Neurotoxicity was frequent in patients receiving >or=15 mg BID. The maximum tolerated dose, 15 mg BID continuously, was associated with late-onset RVO outside the dose-limiting toxicity window. An alternative dose and schedule, 10 mg BID 5 days on/2 days off, was therefore expanded; one RVO event occurred. Three of 48 evaluable patients with melanoma achieved confirmed partial responses; 10 had stable disease >or=4 months. PD-0325901 exposure was generally dose proportional. Doses >or=2 mg BID consistently caused >or=60% suppression of phosphorylated ERK in melanoma. Fifteen patients showed significant decreases (>or=50%) in Ki-67.
PD-0325901 showed preliminary clinical activity. The maximum tolerated dose, based on first cycle dose-limiting toxicities, was 15 mg BID continuously. However, 10 and 15 mg BID continuous dosing and 10 mg BID 5 days on/2 days off schedules were associated with delayed development of RVO; thus, further enrollment to this trial was stopped. Intermittent dose scheduling between 2 and 10 mg BID should be explored to identify a recommended dose with long-term PD-0325901 use.
This essay was originally written in response to German artist Tanja Ostojić’s invitation at the beginning of April, when my city, Wuhan, was in the eye of the maelstrom of the global coronavirus ...pandemic. She hoped to have an inside look into Wuhan’s lockdown. Coincidently, I kept a diary for sixty-six days to document my confinement and my encounters with the lockdown and the disaster. I found writing this text a good opportunity to relate my diary and end this personal ritual. The initial outcome of this work was edited and published on April 5, 2020, by Tanja Ostojić on the blog of the “Misplaced Women?” project. Five months, after many huge changes in the world, in Wuhan and even to myself, I decided to revise and republish this essay.
Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) and ...EGFR-activating mutations. Proton-pump inhibitors decreased dacomitinib exposure. This analysis summarizes the effect of Histamine-2 receptor antagonists (H2RAs) on dacomitinib exposure. A within-patient comparison of the steady-state trough concentrations (C
) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RAs was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption physiologically based pharmacokinetic (PBPK) model was constructed and verified using clinical pharmacokinetic (PK) data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib's PKs. The adjusted geometric mean of the dacomitinib C
of the dacomitinib parent, metabolite and active moiety following co-administration with an H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without an H2RA (
> 0.05). The PBPK modeling showed negligible change in dacomitinib maximum concentration (C
) and area under the drug concentration-time curve (AUC) over 0-24 h after H2RA administration when compared with those administered dacomitinib alone. Co-administration of an H2RA with dacomitinib is not expected to have any clinically relevant effect on dacomitinib exposure.
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