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Abstract Protein tyrosine phosphatase SHP2 activates RAS signaling, which is a novel target for colorectal cancer (CRC) therapy. However, SHP2 inhibitor monotherapy is ineffective for metastatic CRC and a combination therapy is required. In this study, we aimed to improve the antitumor efficacy of SHP2 inhibition and try to explore the resistance mechanism of SHP2 inhibitor. Results showed that WWP1 promoted the proliferation of CRC cells. Genetic or pharmacological inhibition of WWP1 enhanced the effect of SHP2 inhibitor in suppressing tumor growth in vitro and in vivo. WWP1 may mediate feedback reactivation of AKT signaling following SHP2 inhibition. Furthermore, nomogram models constructed with IHC expression of WWP1 and SHP2 greatly improved the accuracy of prognosis prediction for patients with CRC. Our findings indicate that WWP1 inhibitor I3C can synergize with SHP2 inhibitor and is expected to be a new strategy for clinical trials in treating advanced CRC patients.

Abstract Colorectal cancer (CRC) remains a major global cause of cancer-related mortality, lacking effective biomarkers and therapeutic targets. Revealing the critical pathogenic factors of CRC and the underlying mechanisms would offer potential therapeutic strategies for clinical application. G protein signaling (RGS) protein family modulators play essential role within regulating downstream signaling of GPCR receptors, with function in cancers unclear. Our study focused on the expression patterns of RGS proteins in CRC, identifying Regulator of G protein signaling 16 (RGS16) as a prospective diagnostic and therapeutic target. Analyzing 899 CRC tissues revealed elevated RGS16 levels, correlating with clinicopathological features and CRC prognosis by immunohistochemistry (IHC) combined with microarray. We confirmed the elevated RGS16 protein level in CRC, and found that patients with RGS16-high tumors exhibited decreased disease-specific survival (DSS) and disease-free survival (DFS) compared to those with low RGS16 expression. Functional assays demonstrated that RGS16 promoted the CRC progression, knockdown of RGS16 led to significantly increased apoptosis rates of CRC in vitro and in vivo. Notably, we also confirmed these phenotypes of RGS16 in organoids originated from resected primary human CRC tissues. Mechanistically, RGS16 restrained JNK/P38-mediated apoptosis in CRC cells through disrupting the recruitment of TAB2/TAK1 to TRAF6. This study provides insights into addressing the challenges posed by CRC, offering avenues for clinical translation.

Abstract Background Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 2 (APOBEC2) is associated with nucleotide alterations in the transcripts of tumor-related genes which are contributed to carcinogenesis. Expression and prognosis value of APOBEC2 in stomach adenocarcinoma (STAD) remains unclear. Methods The APOBEC2 gene alteration frequency of STAD and APOBEC2 gene expression in STAD and normal tissues were investigated in cBioportal and GEPIA, respectively. We detected expression of APOBEC2, infiltration of CD66b+ tumor-associated neutrophils and CD163+ tumor-associated macrophages in tissue microarrays by immunohistochemistry. APOBEC2 gene expression was explored by western blot and qRT-PCR. Relationships between APOBEC2 and CD66b, CD163, and other clinicopathological characteristics were investigated. Associations among APOBEC2 expression status and patient survival outcome were further analyzed. Results APOBEC2 gene alteration frequency was 5%, and APOBEC2 gene was downexpressed in STAD compared to normal tissues (P

Heat stroke (HS) is a critical condition with extremely high mortality. Heat acclimation (HA) is widely recognized as the best measure to prevent and protect against HS. Preventive administration of oral rehydration salts III (ORSIII) and probiotics have been reported to sustain intestinal function in cases of HS. This study established a rat model of HA that was treated with probiotics-based ORS (ORSP) during consecutive 21-day HA training. The results showed that HA with ORSP could attenuate HS-induced hyperthermia by regulating thermoregulatory response. We also found that HA with ORSP could significantly alleviate HS-induced multiple organ injuries. The expression levels of a series of heat-shock proteins (HSPs), including HSP90, HSP70, HSP60, and HSP40, were significantly up-regulated from the HA training. The increases in intestinal fatty acid binding protein (I-FABP) and D-Lactate typically seen during HS were decreased through HA. The representative TJ proteins including ZO-1, E-cadherin, and JAM-1 were found to be significantly down-regulated by HS, but sustained following HA. The ultrastructure of TJ was examined by TEM, which confirmed its protective effect on the intestinal barrier protection following HA. We also demonstrated that HA raised the intestinal levels of beneficial bacteria Lactobacillus and lowered those of the harmful bacteria Streptococcus through 16S rRNA gene sequencing. These findings suggest that HA with ORSP was proven to improve intestinal thermotolerance and the levels of protective gut microbiota against HS.

We present spectroscopic confirmation of an ultra-massive galaxy (UMG) with $\log(M_\star/M_\odot) = 10.98 \pm 0.07$ at $z_\mathrm{spec} = 4.8947$ in the Extended Groth Strip (EGS), based on deep observations of Ly$\alpha$ emission with Keck/DEIMOS. The ultra-massive galaxy (UMG-28740) is the most massive member in one of the most significant overdensities in the EGS, with four additional photometric members with $\log(M_\star/M_\odot) > 10.5$ within $R_\mathrm{proj} \sim 1$ cMpc. Spectral energy distribution (SED) fitting using a large suite of star formation histories and two sets of high-quality photometry from ground- and space-based facilities consistently estimates the mass of this object to be $\log(M_\star/M_\odot) \sim 11$ with a small standard deviation between measurements ($\sigma = 0.07$). While the best-fit SED models agree on stellar mass, we find discrepancies in the estimated star formation rate for UMG-28740, resulting in either a star-forming or quiescent system. $\mathit{JWST}$/NIRCam photometry of UMG-28740 strongly favors a quiescent scenario, demonstrating the need for high-quality mid-IR observations. Assuming the galaxy to be quiescent, UMG-28740 formed the bulk of its stars at $z > 10$ and is quenching at $z \sim 8$, resulting in a high star formation efficiency at high redshift ($\epsilon \sim 0.2$ at $z \sim 5$ and $\epsilon \gtrsim 1$ at $z \gtrsim 8$). As the most massive galaxy in its protocluster environment, UMG-28740 is a unique example of the impossibly early galaxy problem.

We present rest-frame optical spectra from Keck/MOSFIRE and Keck/NIRES of 16 candidate ultramassive galaxies targeted as part of the Massive Ancient Galaxies at z > 3 Near-Infrared Survey (MAGAZ3NE). These candidates were selected to have photometric redshifts 3 ≲ z _phot 11.7, and well-sampled photometric spectral energy distributions (SEDs) from the UltraVISTA and VIDEO surveys. In contrast to previous spectroscopic observations of blue star-forming and poststarburst ultramassive galaxies, candidates in this sample have very red SEDs implying significant dust attenuation, old stellar ages, and/or active galactic nuclei (AGN). Of these galaxies, eight are revealed to be heavily dust-obscured 2.0 < z < 2.7 galaxies with strong emission lines, some showing broad features indicative of AGN, three are Type I AGN hosts at z > 3, one is a z ∼ 1.2 dusty galaxy, and four galaxies do not have a confirmed spectroscopic redshift. In fact, none of the sample has ∣ z _spec − z _phot ∣ < 0.5, suggesting difficulties for photometric redshift programs in fitting similarly red SEDs. The prevalence of these red interloper galaxies suggests that the number densities of high-mass galaxies are overestimated at z ≳ 3 in large photometric surveys, helping to resolve the “impossibly early galaxy problem” and leading to much better agreement with cosmological galaxy simulations. A more complete spectroscopic survey of ultramassive galaxies is required to pin down the uncertainties on their number densities in the early Universe.

We present an analysis of the number density of galaxies as a function of stellar mass (i.e., the stellar mass function (SMF)) in the COSMOS field at z ∼ 3.3, making a comparison between the SMF in overdense environments and the SMF in the coeval field. In particular, this region contains the Elentári proto-supercluster, a system of six extended overdensities spanning ∼70 cMpc on a side. A clear difference is seen in the high-mass slope of these SMFs, with overdense regions showing an increase in the ratio of high-mass galaxies to low-mass galaxies relative to the field, indicating a more rapid buildup of stellar mass in overdense environments. This result qualitatively agrees with analyses of clusters at z ∼ 1, though the differences between protocluster and field SMFs at z ∼ 3.3 are smaller. While this is consistent with overdensities enhancing the evolution of their member galaxies, potentially through increased merger rates, whether this enhancement begins in protocluster environments or even earlier in group environments is still unclear. Though the measured fractions of quiescent galaxies between the field and overdense environments do not vary significantly, implying that this stellar mass enhancement is ongoing and any starbursts triggered by merger activity have not yet quenched, we note that spectroscopic observations are biased toward star-forming populations, particularly for low-mass galaxies. If mergers are indeed responsible, high-resolution imaging of Elentári and similar structures at these early epochs should then reveal increased merger rates relative to the field. Larger samples of well-characterized overdensities are necessary to draw broader conclusions in these areas.

Six undescribed capnosane-type macrocyclic diterpenes sarcocrassolins A–F (1–6) and one related known analog pavidolide D (7) were isolated from Sarcophyton crassocaule, a soft coral collected off the Nansha Islands, in the South China Sea. Their complete structures, relative configurations and absolute configurations were established through comprehensive spectroscopic analysis, quantum mechanical nuclear magnetic resonance (QM-NMR) and single-crystal X-ray diffraction. Sarcocrassolins D (4) and E (5) showed inhibitory activity against lipopolysaccharide (LPS)-stimulated inflammatory responses in RAW264.7 cells with IC50 values of 76.8 ± 8.0 μM and 93.0 ± 3.8 μM, respectively.

Two undescribed p-terphenyl derivatives, asperterphenylcins A–B (1–2), and two undescribed diphenyl ether derivatives, asperdiphenylcins A–B (3–4), together with three previously described p-terphenyl derivatives—4″-deoxyterprenin (5), terphenyllin (6), and 3″-hydroxyterphenyllin (7)—were obtained from the solid-rice culture of the marine-derived fungus Aspergillus candidus HM5-4, which was isolated from sponges from the South China Sea. Their structures were elucidated by HRESIMS data and NMR spectroscopic analysis. Compound 1 showed a strong inhibitory effect on Neoscytalidium dimidiatum, with an inhibition circle diameter of 31.67 ± 2.36 mm at a concentration of 10.0 µg/disc. Compounds 5 and 7 displayed cytotoxic activity against human chronic myeloid leukemia cells (K562), human liver cancer cells (BEL-7402), human gastric cancer cells (SGC-7901), human non-small cell lung cancer cells (A549) and human HeLa cervical cancer cells, with IC50 values ranging from 3.32 to 60.36 µM, respectively. Compounds 2, 6 and 7 showed potent inhibitory activity against α-glucosidase, with IC50 values of 1.26 ± 0.19, 2.16 ± 0.44 and 13.22 ± 0.55 µM, respectively.

Background: Phosphorylated Focal adhesion kinase (FAK) has been reported to be intimately involved in various malignant tumors. The effect of p-FAK on colorectal cancer (CRC) is still disputable. The purpose of this study is to investigate the role of p-FAK in the prognosis of colorectal cancer.Methods: The clinical significance of p-FAK expression in CRC was evaluated by immunohistochemistry in a large cohort, including carcinoma and para-carcinoma tissues from 908 patients, and normal tissues, adenoma, and metastasis tissues. The correlation between p-FAK expression and CRC occurrence was investigated in tumor and other tissues. Factors contributing to prognosis were evaluated using Kaplan-Meier survival analysis and Cox regression model.Results: p-FAK is apparently overexpressed in CRC and metastasis tissues. Compared with low p-FAK expression, patients with high p-FAK expression had shorter overall survival [hazard ratio (HR), 2.200; 95% confidence interval (CI), 1.265–3.452; p < 0.01] and disease-free survival (HR, 2.004; 95% CI 1.262–3.382; p < 0.01) in multivariate Cox analysis after adjusting other prognostic factors. High p-FAK expression was also related to a worse chemotherapeutic response in patients who achieved adjuvant chemotherapy (p < 0.01).Conclusion: Expression level of p-FAK is an independent risk factor and can serve as a prognostic biomarker for CRC. High p-FAK expression predicts an unfavorable prognosis of CRC as well as poor chemotherapeutic response.

This study aimed to explore novel targets for celastrol sensitization in colorectal cancer (CRC) based on differentially regulated signals in response to high- or low-dose celastrol. Targeting signals were investigated using Western blotting or phosphorylated receptor tyrosine kinase (RTK) arrays. Corresponding inhibitors for the signals were individually combined with low-dose celastrol for the assessment of combined anti-CRC effects, based on proliferation, apoptosis, colony assays, and xenograft models. The potential mechanism for the combination of celastrol and SHP2 inhibition was further examined. Low-dose celastrol (1 µM). However, when combined with an AKT or ERK inhibitor, low-dose celastrol could cooperatively suppress CRC proliferation. Furthermore, failed AKT or ERK inhibition by low-dose celastrol may be due to reactivated RTK-SHP2 signaling with negative feedback. The combination of celastrol and the SHP2 inhibitor resulted in greatly reduced AKT and ERK signals, as well as greater inhibition of CRC growth than celastrol alone. Moreover, the mechanism underlying combination suppression was also involved in the activation of immune cell infiltration (mainly for CD8+ cells) in CRC tissues. Failure to inhibit RTK-SHP2-AKT/ERK signaling contributed to the lack of CRC growth suppression by low-dose celastrol. However, the combination of celastrol and the SHP2 inhibitor resulted in synergistic inhibition of CRC growth and provided a promising therapeutic target.

Accumulating evidence indicates that lncRNAs are potential biomarkers and key regulators of tumor development and progression. The present study aimed to screen abnormal expression lncRNAs and investigate the mechanisms underlying the function in the progression of colorectal cancer (CRC). Potential CRC prognosis-associated dysregulated lncRNAs were screened and identified using bioinformatics analysis. Loss/gain-of-function experiments were performed to detect the biological roles of FAM222A-AS1 in CRC cell phenotypes in vitro and in vivo. The potential microRNAs that interact with FAM222A-AS1 were identified using online tools and were verified using qRT-PCR and luciferase reporter assay. The expression of FAM222A-AS1 is significantly upregulated in CRC tumor samples and cell lines. CRC patients with elevated FAM222A-AS1 expression in the tumor samples had unfavorable overall survival and disease-free survival. Silencing FAM222A-AS1 expression significantly inhibited CRC cell proliferation, migration, and invasion both in vitro and in vivo. Furthermore, FAM222A-AS1 was mainly distributed in the cytoplasm. It may directly bound to miR-let-7f and inhibit its expression and upregulate MYH9. In summary, FAM222A-AS1, as a novel oncogene in CRC, may promote the CRC progression by inhibiting miR-let-7f/MYH9 axis. The FAM222A-AS1/miR-let-7f/MYH9 signaling pathway may be a novel valuable target for inhibiting CRC.

Abstract Purpose Nicotinamide n‐methyltransferase (NNMT) has good biochemical activity and epigenetic regulation, and has been reported as a major metabolic regulator of cancer. The goal of this study was to investigate the significance of stromal NNMT expression in colorectal cancer (CRC). Patients and methods Stromal expression of NNMT in primary CRC, metastasis CRC, and their non‐cancerous tissues from 1088 CRC patients was examined by immunohistochemistry. The associations between stromal NNMT expression and survival outcomes in 967 patients with stage I‐III CRC were further evaluated with Kaplan‐Meier curve and Cox model analyses. Results NNMT expression was mainly sourced from stromal compartments and also elevated in CRC. Patients with high stromal NNMT (IHC‐score ≥ 106) have a worse survival than those patients with low stromal NNMT. In multiple Cox analyses, high expression of stromal NNMT remained as an independent risk factor in CRC for disease‐free survival with a hazard ratio (HR) of 1.415 (95% confidence interval [CI], 1.015‐1.972) and disease‐specific survival with a HR of 5.004 (95% CI, 2.301‐10.883). In addition, high stromal NNMT expression in CRC also indicates the poor survival outcomes in patients with early stage CRC (stage I and II) and in patients who undergo chemotherapy. Conclusion NNMT is mainly located in CRC stromal compartment. High stromal NNMT expression predicts an unfavorable postoperative prognosis.

Three new phenolic compounds, epicocconigrones C–D (1–2) and flavimycin C (3), together with six known phenolic compounds: epicocconigrone A (4); 2-(10-formyl-11,13-dihydroxy-12-methoxy-14-methyl)-6,7-dihydroxy-5-methyl-4-benzofurancarboxaldehyde (5); epicoccolide B (6); eleganketal A (7); 1,3-dihydro-5-methoxy-7-methylisobenzofuran (8); and 2,3,4-trihydroxy-6-(hydroxymethyl)-5-methylbenzyl-alcohol (9), were isolated from fermentation cultures of a deep-sea sediment-derived fungus, Aspergillus insulicola. Their planar structures were elucidated based on the 1D and 2D NMR spectra and HRESIMS data. The absolute configurations of compounds 1–3 were determined by ECD calculations. Compound 3 represented a rare fully symmetrical isobenzofuran dimer. All compounds were evaluated for their α-glucosidase inhibitory activity, and compounds 1, 4–7, and 9 exhibited more potent α-glucosidase inhibitory effect with IC50 values ranging from 17.04 to 292.47 μM than positive control acarbose with IC50 value of 822.97 μM, indicating that these phenolic compounds could be promising lead compounds of new hypoglycemic drugs.

Nine new azaphilones, including penicilazaphilones I–N (1, 2 and 6–9), epi-geumsanol D (3) and penidioxolanes C (4) and D (5) were isolated from the culture of the marine-derived fungus Penicillium sclerotiorum E23Y-1A. The structures of the isolates were deduced from extensive spectroscopic data (1D and 2D NMR), high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) calculations. All the azaphilones from P. sclerotiorum E23Y-1A were tested for their anti-inflammatory and antitumor activities. Penicilazaphilone N (9) showed moderate anti-inflammatory activity with an IC50 value of 22.63 ± 2.95 μM, whereas penidioxolane C (4) exhibited moderate inhibition against human myeloid leukemia cells (K562), human liver cancer cells (BEL-7402), human gastric cancer cells (SGC-7901), human non-small cell lung cancer cells (A549), and human hela cervical cancer cells, with IC50 values of 23.94 ± 0.11, 60.66 ± 0.13, 46.17 ± 0.17, 60.16 ± 0.26, and 59.30 ± 0.60 μM, respectively.

SHP2 mediates signaling from multiple receptor tyrosine kinases (RTKs) to extracellular signal-regulated kinase (ERK) and Ser and Thr kinase AKT, and its inhibitors offer an unprecedented opportunity for cancer treatment. Although the ERK signaling variation after SHP2 inhibition has been well investigated, the AKT signaling variation in colorectal carcinoma (CRC) is still unknown. Therefore, we performed immunohistochemistry and bioinformatics analyses to explore the significance of p-SHP2 in CRC. A panel of CRC cell lines with the SHP2 inhibitor, SHP099, was used to assess the effects on viability and signaling. The inhibitors of AKT and focal adhesion kinase (FAK) signaling were examined in combination with SHP099 as potential strategies to enhance the efficacy and overcome resistance. Frequent resistance to the SHP2 inhibitor was observed in CRC cells, even in those without RAS mutations. We observed rapid adaptive reactivation of the AKT pathway in response to SHP2 inhibition, possibly driven by the reactivation of RTKs or released p-FAK. High baseline p-FAK may also be associated with CRC cell resistance to SHP2 inhibition. Co-inhibition of FAK abrogated the feedback reactivation of AKT in response to SHP2 inhibition. Moreover, the combined inhibition of SHP2 with AKT or FAK resulted in sustained AKT pathway suppression and improved antitumor efficacy in vitro and in vivo. Our study found that reactivation of the AKT pathway is a key mechanism of adaptive resistance to SHP2 inhibition, highlighting the potential significance of AKT and FAK inhibition strategies to enhance the efficacy of SHP2 inhibitors in CRC treatment.

Extracellular and/or intracellular manipulation of pH in tumor may have noticeable potential in cancer treatment. Although the assembly factor genes of V0 domain of the V-ATPase complex are required for intracellular pH homeostasis, their significance in colorectal cancer (CRC) remains largely unknown. Here, we used bioinformatics to identify the candidates from known assembly factor genes of the V0 domain, which were further evaluated by immunohistochemistry (IHC) in CRC and adjacent normal specimens from 661 patients. Univariate and multivariate Cox analyses were used to evaluate factors contributing to prognosis. The effects of variations in the expression of VMA21 on tumor growth were assessed in vitro and in vivo. Of five known assembly factors, only VMA21 showed differential expression between CRC and adjacent normal tissues at both mRNA and protein levels. Patients with high VMA21 expression had higher differentiation grade and longer disease-specific survival (DSS) at stages I–III disease. High VMA21 expression in tumors was also an independent predictor of DSS (hazard ratio, 0.345; 95% confidence interval, 0.123–0.976), with covariates included TNM stage and differentiation grade. VMA21 overexpression decreased CRC growth, whereas VMA21 knockdown increased CRC growth in vitro and in vivo. VMA21 expression suppresses CRC growth and predicts a favorable DSS in patients with stage I-III disease.

Excessive nitrogen (N) application is widespread in Southern China. The effects of N fertilization on soil properties and crop physiology are poorly understood in tropical red loam soil. We conducted a field experiment to evaluate the effect of nitrogen fertilization rates on physiological attributes (chlorophyll, plant metabolic enzymes, soluble matters) on banana leaves, soil properties (soil enzymes, soil organic matter (SOM), soil available nutrients) as well as banana crop yield in a subtropical region of southern China. The N rates tested were 0 (N0), 145 (N145), 248 (N248), 352 (N352), 414 (NFT), and 455 (N455) g N per plant. The correlations among soil factors, leaf physiological factors and crop yield were evaluated. The results indiated that the high rates of N fertilization (NFT and N455) significantly decreased soil available potassium (K) content, available phosphorus (P) content, glutamine synthetase (GS) activity, and soluble protein and sugar contents compared with lower N rates. The N352 treatment had the highest crop yields compared with higher N rates treatments, followed by the N455 treatment. However, there were no significant differences in crop yields among N fertilization treatments. Factor analysis showed that the N352 treatment had the highest integrated score for soil and leaf physiological factors among all treatments. Moreover, the N352 treatment was the most effective in improving carbon and nitrogen metabolism in banana. Crop yield was significantly and positively linearly correlated with the integrated score (r = 0.823, p < 0.05). Path analysis revealed that invertase, SOM and sucrose synthase (SS) had a strong positive effect on banana yield. Canonical correspondence analysis (CCA) suggested that available K, invertase, acid phosphatase and available P were the most important factors impacting leaf physiological attributes. Cluster analysis demonstrated distinct differences in N application treatment related to variations in soil and leaf factors. This study suggested that excessive N fertilization had a negative effect on soil fertility, crop physiology and yield. The lower N rates were more effective in improving crop yield than higher rates of N fertilization. The N rate of 352 g N per plant (N352) was recommended to reduce excess N input while maintaining the higher yield for local farmers’ banana planting.

Background: Patients with severe novel coronavirus disease (COVID-19) can likely develop comorbidities, which can lead to irreversible organ damage and, eventually, death. However, early indicators of disease progression remain unclear. This study aimed to identify early indicators of disease progression to provide a basis for improved prognostic prediction and disease management.Methods: We examined 53 recovered adult COVID-19 patients who were treated at Shanghai Public Health Clinical Center between January 20, 2020, and February 20, 2020. The patients were categorized into the following four groups according to their condition at admission: mild condition (n = 3), moderate (n = 41), severe (n = 7), and critical (n = 2). They were also categorized according to disease progression as mild or moderate conditions that remained stable (n = 26), moderate disease that progressed to severe condition (n = 18), and continuously severe or critical (n = 9). We then focused on investigating the differences in the epidemiological and laboratory indicators between remained stable cases and progressed to severe condition cases.Results: Mild or moderate patients were younger than severe or critical patients. The number of patients with shortness of breath and underlying diabetes and heart disease at admission was higher in the severe or critical group. This group also showed considerably lower or higher values in 28 laboratory indicators. In addition, mild and moderate patients who remained stable were younger than moderate patients progressing to severe disease. Men had a higher risk of disease progression. Patients who progressed had either higher or lower values in 11 laboratory indicators. Survival curve analysis showed that age, procalcitonin, D-dimer, serum C-reactive protein, lactate dehydrogenase, lymphocytes, neutrophils, CD4%, and CD4/CD8 ratio were significant predictors of progression to severe disease.Conclusions: Lactate dehydrogenase, procalcitonin, etc. are early warning indicators of severe COVID-19. Age (>64 years), shortness of breath, past histories of diabetes and heart disease, and abnormality in 28 other indicators at admission are indicative of severe or progression toward severe COVID-19. Meanwhile, abnormalities in 11 indicators and an abnormal coagulation function index at admission are risk factors for progression to severe disease.

Abstract The polarization of tumor‐associated macrophages (TAMs) and tumor‐associated neutrophils (TANs), especially from the antitumoral phenotype to the protumoral phenotype under certain conditions, has an important influence on the progression of tumors. However, the interactions and combined prognosis of these cells are poorly known. Here, we detected the infiltration of CD68+ TAMs, CD163+ TAMs, and CD66b+ TANs in the specimens from 662 patients with GC by immunohistochemistry. The results showed that the infiltration of each of CD163+, CD68+, and CD66b+ cells in GC tissue was significantly increased and independently associated with GC prognosis. Strong collinearity (r = 0.690, P

Tumor-infiltrating immune cells (TIICs) play essential roles in cancer development and progression. However, the association of TIICs with prognosis in colorectal cancer (CRC) patients remains elusive. Infiltration of TIICs was assessed using ssGSEA and CIBERSORT tools. The association of TIICs with prognosis was analyzed in 1,802 CRC data downloaded from the GEO (https://www.ncbi.nlm.nih.gov/geo/) and TCGA (https://portal.gdc.cancer.gov/) databases. Three populations of TIICs, including CD66b+ tumor-associated neutrophils (TANs), FoxP3+ Tregs, and CD163+ tumor-associated macrophages (TAMs) were selected for immunohistochemistry (IHC) validation analysis in 1,008 CRC biopsies, and their influence on clinical features and prognosis of CRC patients was analyzed. Prognostic models were constructed based on the training cohort (359 patients). The models were further tested and verified in testing (249 patients) and validation cohorts (400 patients). Based on ssGSEA and CIBERSORT analysis, the correlation between TIICs and CRC prognosis was inconsistent in different datasets. Moreover, the results with disease-free survival (DFS) and overall survival (OS) data in the same dataset also differed. The high abundance of TIICs found by ssGSEA or CIBERSORT tools can be used for prognostic evaluation effectively. IHC results showed that TANs, Tregs, TAMs were significantly correlated with prognosis in CRC patients and were independent prognostic factors (PDFS ≤ 0.001; POS ≤ 0.023). The prognostic predictive models were constructed based on the numbers of TANs, Tregs, TAMs (C-indexDFS&OS = 0.86; AICDFS = 448.43; AICOS = 184.30) and they were more reliable than traditional indicators for evaluating prognosis in CRC patients. Besides, TIICs may affect the response to chemotherapy. In conclusion, TIICs were correlated with clinical features and prognosis in patients with CRC and thus can be used as markers.

As an important way to help express the preference relation between alternatives, distributed preference relation (DPR) can represent the preferred, non-preferred, indifferent, and uncertain degrees of one alternative over another simultaneously. DPR, however, is unavailable in some situations where a decision maker cannot provide the precise degrees of one alternative over another due to lack of knowledge, experience, and data. In this paper, to address this issue, we propose interval-valued DPR (IDPR) and present its properties of validity and normalization. Through constructing two optimization models, an IDPR matrix is transformed into a score matrix to facilitate the comparison between any two alternatives. The properties of the score matrix are analyzed. To guarantee the rationality of the comparisons between alternatives derived from the score matrix, the additive consistency of the score matrix is developed. In terms of these, IDPR is applied to model and solve multiple criteria group decision making (MCGDM) problem. Particularly, the relationship between the parameters for the consistency of the score matrix associated with each decision maker and those for the consistency of the score matrix associated with the group of decision makers is analyzed. A manager selection problem is investigated to demonstrate the application of IDPRs to MCGDM problems.

OBJECTIVES: We aimed to determine the associations of genetic polymorphisms of excision repair cross-complementation group 1 (ERCC1) rs11615, xeroderma pigmentosum group D (XPD/ERCC2) rs13181, X-ray repair cross complementing group 1 (XRCC1) rs25487, XRCC3 rs1799794, and breast cancer susceptibility gene 1 (BRCA1) rs1799966 from the DNA repair pathway and multiple drug resistance 1 (MDR1/ABCB1) rs1045642 with response to chemotherapy and survival of non-small cell lung cancer (NSCLC) in a Chinese population. MATERIALS AND METHODS: A total of 352 NSCLC patients were enrolled to evaluate the associations of the six SNPs with response to chemotherapy and overall survival. Logistic regressions were applied to test the associations of genetic polymorphisms with response to chemotherapy in 161 advanced NSCLC patients. Overall survival was analyzed in 161 advanced and 156 early stage NSCLC patients using the Kaplan-Meier method with log-rank test, respectively. Multivariate Cox proportional hazards model was performed to determine the factors independently associated with NSCLC prognosis. RESULTS: BRCA1 rs1799966 minor allele C (TC+CC vs. TT, OR = 0.402, 95% CI = 0.204-0.794, p = 0.008) and MDR1/ABCB1 rs1045642 minor allele A (GA +AA vs. GG, OR = 0.478, 95% CI = 0.244-0.934, p = 0.030) were associated with a better response to chemotherapy in advanced NSCLC patients. Survival analyses indicated that BRCA1 rs1799966 TC+CC genotypes were associated with a decreased risk of death (HR = 0.617, 95% CI = 0.402-0.948, p = 0.028) in advanced NSCLC patients, and the association was still significant after the adjustment for covariates. Multivariate Cox regression analysis showed that ERCC1 rs11615 AA genotype (P = 0.020) and smoking (p = 0.037) were associated with increased risks of death in early stage NSCLC patients after surgery. CONCLUSIONS: Polymorphisms of genes in DNA repair pathway and MDR1 could contribute to chemotherapy response and survival of patients with NSCLC.

BACKGROUND: Disaster is a serious public health issue. Health professionals and community residents are main players in disaster responses but their knowledge levels of disaster medicine are not readily available. This study aimed to evaluate knowledge levels and training needs of disaster medicine among potential disaster responders and presented a necessity to popularize disaster medicine education. METHODS: A self-reporting questionnaire survey on knowledge level and training needs of disaster medicine was conducted in Shanghai, China, in 2012. A total of randomly selected 547 health professionals, 456 medical students, and 1,526 local residents provided intact information. The total response rate was 93.7%. RESULTS: Overall, 1.3% of these participants have received systematic disaster medicine training. News media (87.1%) was the most common channel to acquire disaster medicine knowledge. Although health professionals were more knowledgeable than community residents, their knowledge structure of disaster medicine was not intact. Medical teachers were more knowledgeable than medical practitioners and health administrators (p = 0.002). Clinicians performed better than public health physicians (p