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Supplementary Data from A Genomic Approach to Improve Prognosis and Predict Therapeutic Response in Chronic Lymphocytic Leukemia

Purpose: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a variable clinical course. Several parameters have prognostic capabilities but are associated with altered response to therapy in only a small subset of patients.Experimental Design: We used gene expression profiling methods to generate predictors of therapy response and prognosis. Genomic signatures that reflect progressive disease and responses to chemotherapy or chemoimmunotherapy were created using cancer cell lines and patient leukemia cell samples. We validated and applied these three signatures to independent clinical data from four cohorts, representing a total of 301 CLL patients.Results: A genomic signature of prognosis created from patient leukemic cell gene expression data coupled with clinical parameters significantly differentiated patients with stable disease from those with progressive disease in the training data set. The progression signature was validated in two independent data sets, showing a capacity to accurately identify patients at risk for progressive disease. In addition, genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were generated and could accurately distinguish responding and nonresponding CLL patients.Conclusions: Thus, microarray analysis of CLL lymphocytes can be used to refine prognosis and predict response to different therapies. These results have implications for standard and investigational therapeutics in CLL patients. (Clin Cancer Res 2009;15(22):694755)

A series of quinoxaline-2-thiols and quinoxalines were prepared in moderate to good yields from various phenacyl sulfoxides bearing 1-methyl-1H-tetrazole and o-arylenediamines. The proposed reaction mechanism involves generation of sulfines from the phenacyl sulfoxides bearing 1-methyl-1H-tetrazole through thermolysis elimination. Then, site-selective carbophilic addition of sulfines by o-arylenediamines, followed by elimination, intramolecular nucleophilic addition, and dehydration condensation. The current method provides a direct and simple strategy for the preparation of quinoxaline-2-thiols and quinoxalines.

The developed method can be used for analyzing the δ34S of pyrite samples with a limited analyzable region (>1 × 1 μm2) with high precision in nano-scale secondary ion mass spectroscopy.

SmCo5 magnets were prepared by spark plasma sintering (SPS) technique. The phase constitutions, magnetic properties, and microstructures of magnets prepared under different sintering temperatures were investigated systematically. It is observed that the 1:5 phase and 2:7 phase coexist in the magnet, and 2:17 phase appears when the temperature rises to 1050 °C. The best magnetic properties were obtained for the magnets prepared at 1000 °C, with remanence Jr = 0.45 T, intrinsic coercivity Hcj = 985 kA/m, and maximum energy density (BH)max = 37 kJ/m3. It is shown that the SPSed magnet prepared at 1000 °C exhibits excellent thermal stability which is described in terms of temperature coefficient of remanence (α) = −0.15%/°C and temperature coefficient of coercivity (β) = −0.25%/°C in the temperature range of 27–400 °C. The microstructure analysis showed that the high density of the magnet and the uniform distribution of the hard magnetic phase are the main reasons for the excellent magnetic properties.

NdFeB hot-pressed and hot-deformed magnets were prepared by hot-pressed (HP) sintering and spark plasma sintering (SPS). The effects of sintering mechanisms of SPS and HP on the microstructure of hot deformation magnets were studied. The temperature of the mold surface is much higher than that of the sample in the cavity in HP, but lower than that of the sample in SPS. The Nd-rich phase is uniformly distributed and the grain size is smaller in the hot-deformed magnets prepared by HP, while the Nd-rich phase is excessively enriched and the grain size in the liquid-enriched region is abnormal in the hot-deformed magnets prepared by SPS. The comprehensive magnetic properties of hot deformed magnets prepared by SPS are significantly lower than those prepared by HP.

In the era of big data, the impact of the massive public opinion information generated by the Internet on the securities market has become a factor that can't be ignored in investment decision-making and supervision. Under the influence of these factors, investors are influenced and restricted by psychology, self-cognition and limited attention, which will make them pay different attention to stocks, which spread to the securities market, and then have an impact on the market performance of individual stocks. This paper selects big data's public opinion information from securities websites, authoritative media data and mainstream social networking sites designated by China Shenzhen Stock Exchange to quantify the Internet attention index. According to different subjects and angles, it is divided into: media attention, netizens' attention, public opinion attention. Based on these three kinds of attention index data, this paper establishes the panel regression model and the GARCH (1, 1) model of the influence of different subject attention on individual stocks, and introduces abnormal media attention, abnormal netizens' attention, abnormal public opinion attention, lag attention and change of attention into the model to empirically test the three main market manifestations of individual stocks, namely, earnings, liquidity and volatility. Through comprehensive analysis and research, this paper discusses in detail and comprehensively the internal mechanism of the influence of Internet attention on the performance of individual stocks in China's securities market under the environment of big data. The conclusion of the study provides a reference for investor decision-making, market capitalization maintenance of listed companies and supervision of financial institutions.

This study aimed to evaluate the effect of reinforced education (RE) by short message service (SMS) on the bowel preparation quality of patients undergoing colonoscopy.Randomized controlled trials (RCTs), conducted on the effect of RE by SMS on bowel preparation for colonoscopy from inception to November 1, 2021, were queried from databases, including PubMed, Web of Science, the Cochrane Library, and EMBASE. After extracting the data, meta-analysis was conducted using Review Manager Software version 5.3.A total of seven RCTs with 5889 patients were subjected to meta-analysis. The rate of adequate bowel preparation in the SMS group (81.7%) was significantly higher than that in the control group (75.7%) (RR: 1.10, 95% CI: 1.03-1.17, p 0.01). Four studies suggested that RE by SMS significantly reduced the non-attendance rate of patients for scheduled colonoscopy (RR: 0.74, 95% CI: 0.56-0.99, p 0.05).RE by SMS for patients undergoing colonoscopy can significantly improve the quality of bowel preparation and decrease the non-attendance rate of patients for scheduled colonoscopy.

Actinomycete strain YIM PH20352, isolated from the rhizosphere soil sample of Panax notoginseng collected in WenShang, Yunnan Province, China, exhibited antifungal activity against some phytopathogenic fungi. The structures of bioactive molecules, isolated from the ethyl acetate extract of the fermentation broth of the strain, were identified as rabelomycin (1) and dehydrorabelomycin (2) based on extensive spectroscopic analyses. Compound 1 exhibited antifungal activity against four tested root-rot pathogens of the Panax notoginseng including Plectosphaerella cucumerina, Alternaria panax, Fusarium oxysporum, and Fusarium solani with the MIC values at 32, 64, 128, and 128 μg/mL, respectively. Compound 2 exhibited antifungal activity against F. oxysporum, P. cucumerina, F. solani, and A. panax with the MIC values at 64, 64, 128, and 128 μg/mL, respectively. Based on the phylogenetic analyses, the closest phylogenetic relative of strain YIM PH20352 is Streptomyces cellulosae NBRC 13027

A layer of glycocalyx covers the vascular endothelium serving important protective and homeostatic functions. The objective of this study was to determine if breakdown of the endothelial glycocalyx (eGC) occurs during malaria infection in children. Measures of eGC integrity, endothelial activation, and microvascular reactivity were prospectively evaluated in 146 children: 44 with moderately severe malaria (MSM), 42 with severe malaria (SM), and 60 healthy controls (HC). Biochemical measures of eGC integrity included plasma syndecan-1 and total urinary glycosaminoglycans (GAG). Side-stream dark field imaging was used to quantitatively assess integrity of eGC. Plasma angiopoietin-2 (Ang-2) was measured as a marker of endothelial activation and also as a possible mediator of eGC breakdown. Our results show that urinary GAG, syndecan-1, and Ang-2 were elevated in patients with MSM and SM compared with HC. Syndecan-1 and GAG levels correlated significantly with each other and with plasma Ang-2. The eGC breakdown products also inversely correlated significantly with hemoglobin and platelet count. In the MSM group, imaging results provided further evidence for eGC degradation. Although not correlated with markers of eGC degradation, vascular function (assessed by non-invasive near infrared spectroscopy [NIRS]) demonstrated reduced microvascular reactivity, particularly affecting the SM group. Our findings provide further evidence for breakdown of eGC in falciparum malaria that may contribute to endothelial activation and adhesion of parasitized red blood cells, with reduced nitric oxide formation, and vascular dysfunction.

Cerebral malaria (CM) from Plasmodium falciparum infection is associated with endothelial dysfunction and parasite sequestration. The glycocalyx (GCX), a carbohydrate-rich layer lining the endothelium, is crucial in vascular homeostasis. To evaluate the role of its loss in the pathogenesis of pediatric CM, we measured GCX degradation in Tanzanian children with World Health Organization–defined CM (n = 55), uncomplicated malaria (UM; n = 20), and healthy controls (HCs; n = 25). Urine GCX breakdown products [glycosaminoglycans (GAGs)] were quantified using dimethylmethylene blue (DMMB) and liquid chromatography–tandem mass spectrometry assays. DMMB-GAG and mass spectrometry (MS)-GAG (g/mol creatinine) were increased in CM and UM compared with HCs (P < 0.001), with no differences in DMMB-GAG and MS-GAG between CM and UM children or between those with and without a fatal outcome. In CM survivors, urinary GCX DMMB-GAG normalized by d 3. After adjusting for disease severity, DMMB-GAG was significantly associated with parasitemia [partial correlation coefficient (P(corr)) = 0.34; P = 0.01] and plasma TNF (P(corr) = 0.26; P = 0.04) and inversely with plasma and urine NO oxidation products [P(corr) = −0.31 (P = 0.01) and P(corr) = −0.26 (P = 0.03), respectively]. GCX breakdown is increased in children with falciparum malaria, with similar elevations in CM and UM. Endothelial GCX degradation may impair endothelial NO production, exacerbate adhesion-molecule expression, exposure, and parasite sequestration, and contribute to malaria pathogenesis.—Yeo, T. W., Bush, P. A., Chen, Y., Young, S. P., Zhang, H., Millington, D. S., Granger, D. L., Mwaikambo, E. D., Anstey, N. M., Weinberg, J. B. Glycocalyx breakdown is increased in African children with cerebral and uncomplicated falciparum malaria.

Background: Interactions between the endothelium and infected erythrocytes play a major role in the pathogenesis of falciparum malaria, with microvascular dysfunction and parasite sequestration associated with worsening outcomes. The glycocalyx is a carbohydrate-rich layer that lines the endothelium, with multiple roles in vascular homeostasis. The role of the glycocalyx in falciparum malaria and the association with disease severity has not been investigated. Methods: We prospectively enrolled Indonesian inpatients (aged ≥18 years) with severe (SM) or moderately severe (MSM) falciparum malaria, as defined by World Health Organization criteria, and healthy controls (HCs). On enrollment, blood and urine samples were collected concurrently with measurements of vascular nitric oxide (NO) bioavailability. Urine was assayed for glycocalyx breakdown products (glycosaminoglycans) using a dimethylmethylene blue (GAG-DMMB) and liquid chromatography-tandem mass spectrometry (GAG-MS) assay. Results: A total of 129 patients (SM = 43, MSM = 57, HC=29) were recruited. GAG-DMMB and GAG-MS (g/mol creatinine) were increased in SM (mean, 95% confidence interval: 3.98, 2.44–5.53 and 6.82, 5.19–8.44) compared to MSM patients (1.78, 1.27–2.29 and 4.87, 4.27–5.46) and HCs (0.22, 0.06–0.37 and 1.24, 0.89–1.59; P < 0.001). In SM patients, GAG-DMMB and GAG-MS were increased in those with a fatal outcome (n = 3; median, interquartile range: 6.72, 3.80–27.87 and 12.15, 7.88–17.20) compared to survivors (n = 39; 3.10, 0.46–4.5 and 4.64, 2.02–15.20; P = 0.03). Glycocalyx degradation was significantly associated with parasite biomass in both MSM (r = 0.48, GAG-DMMB and r = 0.43, GAG-MS; P < 0.001) and SM patients (r = 0.47, P = 0.002 and r = 0.33, P = 0.04) and inversely associated with endothelial NO bioavailability. Conclusions: Increased endothelial glycocalyx breakdown is associated with severe disease and a fatal outcome in adults with falciparum malaria. National Medical Research Council (NMRC) Published version The study was supported by the National Health and Medical Research Council of Australia (grants 1132975, International Collaborative Research Grant 283321, HOTNORTH 1131932 [E. K.] and Fellowship 1135820 [N. A.]), the National Institutes of Health (grant 1R01 HL130763-01), the Durham VA Research Service (2772), the Wellcome Trust (ICRG ME928457MES), and the Singapore National Medical Research Council (award to T. W. Y., CSA INV 15nov007).

Objectives Chemotheraputic drug resistance is a critical factor associated with the poor survival in advanced/metastatic pancreatic cancer (PC) patients. Methods Human pancreatic cell lines Capan-1 and BXPC-3 were cultured with different concentrations of erlotinib (0, 10, 50, and 100 μm) for 48 h. The relative cell viability and apoptosis was detected using MTT assays and flow cytometry apoptosis analysis, respectively. Transfection of pcDNA-EphA2, si-EphA2 and miR-124 mimic/inhibitor was used to modulate the intracellular level of EphA2 and miR-124. The interaction between miR-124 and the 3′UTR of EphA2 was explored using dual luciferase reporter assay. Key findings Compared with BXPC-3 cells, Capan-1 cells showed resistance to differential concentration treatment of erlotinib. The expression of EphA-2 was significantly increased and the expression of miR-124 was significantly decreased in Capan-1 cells. Overexpressing EphA2 induced resistance of BXPC-3 cells to erlotinib treatment. And EphA2 was identified as a novel target gene for miR-124. MiR-124 overexpression was able to sensitize the response of Capan-1 cells to erlotinib through inhibiting EphA2. Furthermore, both miR-124 overexpression and EphA2 inhibition sensitized Capan-1 cells to erlotinib in xenograft model. Conclusions Our study demonstrated that EphA2 rescued by miR-124 downregulation conferred the erlotinib resistance of PC cell Capan-1 with K-RAS mutation.

Background Colorectal juvenile polyps are rare and generally considered benign in adults. Carcinogenesis or neoplastic changes are rarely mentioned in the literature. We systematically evaluated the characteristics and potential malignancy of colorectal juvenile polyps in adults. Methods We retrospectively reviewed the medical records of 103 adults diagnosed with colorectal juvenile polyps from September 2007 to May 2020 at our hospital. The characteristics, endoscopic findings, occurrence of intraepithelial neoplasia, carcinogenesis and diagnostic value of chicken skin mucosa (CSM) were analyzed. Results The average age of patients with juvenile polyps was 43.2 years (range, 19 to 78 years). A total of 101 patients (101/103, 98.1%) had a single juvenile polyp, and two patients had multiple polyps (107 polyps in total). Polyp sizes ranged from 0.5 to 5 cm. One (1/107, 0.9%) juvenile polyp was cancerous, and 7 (7/107, 6.5%) developed low-grade intraepithelial neoplasia. Neoplasia and cancerization did not appear in the two patients with multiple polyps. A 27-year-old female had a 2-cm polyp with well-differentiated adenocarcinoma in the mucosa in the sigmoid colon with erosion on the surface. CSM was observed adjacent to 17 polyps, which were all located in the rectum and sigmoid colon, and one polyp showed low-grade intraepithelial neoplasia. Conclusions Colorectal juvenile polyps occur in a wide range of locations and in variable sizes and numbers. These polyps are solitary in most patients and have neoplastic potential. CSM is not a tumorigenic marker in colorectal juvenile polyps and usually occurs in the distant colorectum. Colorectal juvenile polyps in adults may progress from low-grade intraepithelial neoplasia to high-grade intraepithelial neoplasia and then to carcinoma and should be treated when discovered and regularly followed as colorectal adenomas.

Degradation of the endothelial glycocalyx is associated with mortality in adult falciparum malaria. However, its role in the pathogenesis of non-falciparum malaria is unknown. In Malaysian patients with knowlesi (n = 200) and vivax (n = 61) malaria, and in healthy controls (n = 50), we measured glycocalyx breakdown products plasma syndecan-1 and urinary glycosaminoglycans, and evaluated correlations with biomarkers of disease severity. Urinary glycosaminoglycans were increased in patients with knowlesi and vivax malaria compared to healthy controls, and in knowlesi malaria were highest in those with severe disease. In knowlesi malaria, plasma syndecan-1 was also highest in those with severe disease, and correlated with markers of endothelial activation (angiopoietin-2, osteoprotegerin, ICAM-1), asymmetric dimethylarginine (ADMA) and impaired microvascular reactivity. Syndecan-1 also correlated with endothelial activation (ICAM-1, angiopoietin-2) and ADMA in vivax malaria. In knowlesi malaria increased syndecan-1 was associated with acute kidney injury, after controlling for age and parasitemia. In knowlesi malaria, the difference in median syndecan-1 between severe and non-severe disease was more marked in females than males. Endothelial glycocalyx degradation is increased in knowlesi and vivax malaria, and associated with disease severity and acute kidney injury in knowlesi malaria. Agents that inhibit glycocalyx breakdown may represent adjunctive therapeutics for severe non-falciparum malaria. Published version Tis work supported by the National Health and Medical Research Council of Australia (Program Grants 1132975, Project Grant 1098334 and fellowships to BEB [1088738], MJG [1138860], and NMA [1135820]), and the National Institutes of Health (Grant R01 HL130763-01). Te Sabah malaria research program is supported by US National Institutes of Health (R01 AI116472-03).

Alteration in RNA splicing is implicated in carcinogenesis and progression. Mutations in spliceosome genes and alternative splicing of other genes have been noted in chronic lymphocytic leukaemia (CLL), a common B cell malignancy with heterogeneous outcomes. We previously demonstrated that differences in the amount of SET oncoprotein (a physiological inhibitor of the serine/threonine phosphatase, PP2A) is associated with clinical aggressiveness in patients with CLL. It is unknown if alternative splicing of gene transcripts regulating kinases and phosphatases affects disease pathobiology and CLL progression. We show here for the first time that mRNA levels of the alternatively spliced SET isoforms, SETA and SETB (SETα and SETβ), significantly correlate with disease severity (overall survival and time-to-first-treatment) in CLL patients. In addition, we demonstrate that relative increase of SETA to SETB mRNA can discriminate patients with a more aggressive disease course within the otherwise favourable CLL risk classifications of IGHV mutated and favourable hierarchical fluorescence insitu hybridisation groups. We validate our finding by showing comparable relationships of SET mRNA with disease outcomes using samples from an independent CLL cohort from a separate institution. These findings indicate that alternative splicing of SET, and potentially other signalling cascade molecules, influences CLL biology and patient outcomes.

Cytokines play important roles in tumorigenesis and progression of cancer cells, while their functions in drug resistance remain to be illustrated. We successfully generated doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (namely HCT-116/Dox and SW480/Dox, respectively). Cytokine expression analysis revealed that IL-8, while not FGF-2, EGF, TGF-β, IL-6, or IL-10, was significantly increased in Dox-resistant CRC cells as compared with their corresponding parental cells. Targeted inhibition of IL-8 via siRNAs or its inhibitor reparixin can increase the Dox sensitivity of HCT-116/Dox and SW480/Dox cells. The si-IL-8 can decrease the mRNA and protein expression of multidrug resistance 1 (MDR1, encoded by ABCB1), while has no effect on the expression of multidrug resistance-associated protein 1 (ABCC1), in CRC Dox-resistant cells. IL-8 can increase the phosphorylation of p65 and then upregulate the binding between p65 and promoter of ABCB1. BAY 11-7082, the inhibitor of NF-κB, suppressed the recombination IL-8 (rIL-8) induced upregulation of ABCB1. It confirmed that NF-κB is involved in IL-8-induced upregulation of ABCB1. rIL-8 also increased the phosphorylation of IKK-β, which can further activate NF-κB, while specific inhibitor of IKK-β (ACHP) can reverse rIL-8-induced phosphorylation of p65 and upregulation of MDR1. These results suggested that IL-8 regulates the Dox resistance of CRC cells via modulation of MDR1 through IKK-β/p65 signals. The targeted inhibition of IL-8 might be an important potential approach to overcome the clinical Dox resistance in CRC patients.

In this work, Sm24.6Co50Fe17·4Cu5·7Zr2.3-xHfx (x = 0–2.0) ribbons and magnets were prepared by melt-spinning method and spark plasma sintering (SPS) technique. The magnetic properties of the melt-spun ribbons with Hf addition are much higher than those of the Hf-free ribbons in the temperature range of 300–400 K. The optimal comprehensive magnetic properties of ribbons and isotropic magnets were obtained with 1.0 wt% Hf substitution. Microstructural results showed that Hf elements do not enter into the hard magnetic 1:7H and 2:17R phase in SPSed magnets and Zr–Hf rich phases are formed around grain boundaries as particulates. The enhancement of magnetic properties of the ribbons and SPSed magnets can be attributed to grain refinement and more uniform microstructure as a result of Hf addition. The micro-twin structure of 2:17R phase also have been discovered in the spark plasma sintered magnets. This work may provide a rapid preparation of Sm2Co17 magnets.

Anthranilic diamides are one of the most important classes of modern agrochemical insecticides. To discover new structures with higher activity, lower toxicity and lower residue, a series of novel anthranilic diamides containing dihydroisoxazoline and isoxazole was designed and synthesized. Their structures were characterized by means of melting points, proton nuclear magnetic resonance(1H NMR), 13C NMR and high resolution mass spectrometry(HRMS). According to the bioassay data, it was found that some of the title compounds exhibit moderate insecticidal activity and good antifungal activity. In particularly, compound 15b with a concentration of 50 mg/L shows a lethality rate of 60.0% against Mythimna separata Walker and a lethality rate of 50.0% against Culex pipiens pallens with a concentration of 1 mg/L. Moreover, compound 15b showed good antifungal activities(58.8%, 77.1%, 70.7%, 55.3%, 60.7%, 65.4%) when against all the tested fungi(Cercospora arachidicola Hori, Physalospora piricola, Rhizoctonia cerealis, Bipolaris maydis, Watermelon anthracnose, Fusarium moniliforme). The effects of compounds 14h, 14j and 15b on the concentration of intracellular calcium ion([Ca2+]i) in the central neurons of Mythimna separate Walker were well investigated via calcium imaging technique. The results demonstrate that the novel compounds can elevate the calcium concentration in the neurons, denoting that some new structures are potential modulators of the insect ryanodine receptor(RyR).

Based on the structure of natural product 2-aryl-4,5-dihydrothiazole-4-carboxylic acid, a series of novel (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives were designed and synthesized. Their structures were characterized by 1H NMR, 13C NMR and HRMS. The single crystal structure of compound 9b was determined by X-ray diffraction analysis. The antifungal activities were evaluated for the first time. The bioassay results indicated that most compounds exhibited moderate to good antifungal activities. The antifungal activities of compound 13a (against Cercospora arachidicola Hori), 13d (against Alternaria solani), and 16e (against Cercospora arachidicola Hori) were 61.9%, 67.3% and 61.9%, respectively, which are higher than those of the commercial fungicides chlorothalonil and carbendazim. Moreover, compound 13d exhibited excellent antifungal activities against 7 kinds of the fungi tested (66.7%, 77.3%, 63.0%, 87.9%, 70.0%, 70.0% and 80.0% at 50 µg?mL). Therefore, 13d can be used as a new lead structure for the development of antifungal agents.

Sulfonylureas(SUs) are potent and selective inhibitors of acetohydroxyacid synthase and has been used as herbicides. Some SUs also displayed other biological activities. In order to discuss the antifungal activity of SUs, a series of novel SUs containing aryl-substituted pyrimidine moieties was designed and synthesized. The preliminary bioassay showed that the title compounds exhibited moderate to favorable fungicidal activities in vivo. Especially, compound 9b exhibited more efficacy than the controls against five fungi at 25 mg/L. These promising results indicate that an aryl group on pyrimidine ring is favorable for antifungal activity and SUs are potential inhibitors for some phytopathogenic fungi.