Zeitschriftenartikel: „ERx“

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Viswanadhapalli, Suryavathi, Xihui Liu, Uday Pratap, Gangadhara R. Sareddy, Susan T. Weintraub, Ganesh V. Raj, Jung-Mo Ahn und Ratna K. Vadlamudi. „Abstract P6-10-14: Lysosomal acid lipase (LIPA) as a novel therapeutic vulnerability for treating TNBC“. Cancer Research 83, Nr. 5_Supplement (01.03.2023): P6–10–14—P6–10–14. http://dx.doi.org/10.1158/1538-7445.sabcs22-p6-10-14.

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Abstract Background: TNBCs have the highest mortality rate among all BC subtypes. There is thus an urgent and unmet need for effective targeted therapies in TNBC. Recently we, identified a novel agent ERX-41 that showed good efficacy in treating TNBC in preclinical mouse models, however, its molecular action remain unknown. In this study, we identified LIPA as novel molecular target of ERX-41. Methods: We have used CRISPR knockout pooled library and multiple TNBC models for identifying molecular target of ERX-41. Mechanistic studies were performed using LIPA mutants, RNA-seq, Turbo-ID mapping, Mass spectrometry, Immunoprecipitation, and Western blotting. The in vivo efficacy of ERX-41 was examined using four different patient-derived xenograft (PDX) models. We evaluated LIPA protein expression in TNBC using tissue microarray (TMA). Results: To identify the molecular target of ERX-41, we performed an unbiased CRISPR–Cas9 knockout (KO) screen in MDA-MB-231 cells and the results identified LIPA as a top hit. KO of LIPA alone (which encodes lysosomal acid lipase (LAL) abrogated cytotoxic response to ERX-41. Cellular thermal shift assays confirmed that ERX-41 binds to LAL. In silico modelling and mutational studies confirmed that ERX-41 interacts with LAL through residues in its LXXLL domain and that ERX-41 ability to induce ER stress and cell death in TNBC is independent of the lipase activity of LAL. Unbiased RNA-seq studies with and without ERX-41 in parental and LIPA KO SUM-159 cells revealed induction of genes involved in ER stress and UPR response by ERX-41 in parental SUM-159 cells but not in cells with LIPA KO. Ultrastructural studies using live-cell confocal microscopy show that LIPA KO abrogated ER morphological changes at 2 and 4 h after ERX-41 treatment. Further, subcellular localization studies showed LIPA localizes to endoplasmic reticulum (ER). Unbiased proteomic approaches (TurboID and DIA mass spec) identified a core set of proteins that were both LAL binders and affected by ERX-41 treatment. GO analyses of LAL binding proteins confirmed their involvement in protein folding. Tumor micro array (TMA) analyses confirmed that >80% of primary TNBC tumors had significant and detectable LAL protein expression in contrast, normal breast tissue had lower LAL expression. ERX-41 (10 mg/kg body weight) decreased growth of four distinct TNBC patient-derived xenografts (PDXs) in vivo. Conclusions: Our results identified a new molecular target (LAL) for ERX-41 and novel mechanism of action (disruption of protein folding and induction of ER stress) that may have utility in treating patients with TNBC. Citation Format: Suryavathi Viswanadhapalli, Xihui Liu, Uday Pratap, Gangadhara R. Sareddy, Susan T. Weintraub, Ganesh V. Raj, Jung-Mo Ahn, Ratna K. Vadlamudi. Lysosomal acid lipase (LIPA) as a novel therapeutic vulnerability for treating TNBC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-14.

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Viswanadhapalli, Suryavathi, Tae-Kyung Lee, Kara Kassees, Gaurav Sharma, Rahul Gopalam, Karla Parra, Tanner Reese et al. „Abstract 4813: ERX-208 as a novel therapeutic for treating ovarian cancer by enhancing endoplasmic reticulum stress“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 4813. http://dx.doi.org/10.1158/1538-7445.am2023-4813.

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Abstract Background: Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. Despite initial response to chemotherapy, most OCa patients become chemo resistant and progress to metastatic disease. Here, we tested the hypothesis that the high basal level of endoplasmic reticulum stress (ERS) in OCa represents a critical vulnerability and drugs that further aggravate this already engaged system in OCa may exhaust its protective features and contribute to apoptosis induction. The objective of this proposal is to identify a hit compound that enhances ERS in OCa and to conduct mechanistic studies. Methods: We synthesized a small library of >200 chemically distinct oligobenzamide analogs with maintenance of the chemical backbone but altered R groups of ERX-11. We performed the primary screening of this library to evaluate the induction of mRNA levels of two canonical ERS/UPR (unfolded protein response) genes- sXBP1 and CHOP. Biological activity of ERX-208 was validated using multiple OCa cells. Mechanistic studies were conducted using CRISPR/Cas9 KO, Western blotting, reporter gene assays, IHC and RNA-seq analysis. PK (pharmacokinetics) and toxicity studies were done using C57BL/6 mice. Cell line-derived xenografts (CDXs), patient-derived xenografts (PDXs), patient-derived explants (PDEs), and patient-derived organoids (PDO) were used for preclinical evaluation. Results: From a screen of a curated ERX-11 derived oligobenzamide library, we identified a hit compound, ERX-208 that potently (IC50~100nM) induces ERS/UPR and apoptosis in multiple OCa cells in vitro. CRISPR KO screen identified the lysosomal acid lipase A (LIPA) protein as the critical target of ERX-208. LIPA KO abrogates response to ERX-208, while reconstitution of LIPA restores ERX-208 response. The time course studies showed a robust and consistent induction (>15-fold CHOP, and >10-fold sXBP1) by ERX-208 treatment within 24h. We confirmed induction of classic UPR components peIF2α, CHOP and LC3B using Western blotting in multiple OCa cells. Functionally, ERX-208 causes growth inhibition of OCa cells, as noted by MTT cell viability assays using 15 OCa cells with an IC50 of ~50-100nM. The activity of ERX-208 is distinct among oligobenzamides as ERX-11 has limited/no activity against OCa cells. RNA-seq analysis confirmed that ERX-208 induces significant ERS, UPR, and apoptosis. Further, ERX-208 reduced the growth of OCa PDO’s in vitro, PDEs ex vivo and CDXs and PDXs in vivo. ERX-208 treatment did not show any signs of toxicity and body weight of mice was not affected. IHC analyses showed increased activation of ERS/UPR markers such as GRP78, p-PERK and decreased proliferation measured by Ki67. Conclusions: Collectively, our results demonstrated the utility of ERX-208 and will establish a novel therapeutic paradigm in OCa that overcomes tumor heterogeneity by targeting LIPA and enhancing ERS leading to apoptosis. Citation Format: Suryavathi Viswanadhapalli, Tae-Kyung Lee, Kara Kassees, Gaurav Sharma, Rahul Gopalam, Karla Parra, Tanner Reese, Michael Hsieh, Uday P. Pratap, Xue Yang, Behnam Ebrahimi, Chia Yuan Chen, Scott Terry Elmore, Christian Cervantes, Zhenming Xu, Edward Kost, Gangadhara Reddy Sareddy, Rajeshwar Rao Tekmal, Jung-Mo Ann, Ganesh V. Raj, Ratna K. Vadlamudi. ERX-208 as a novel therapeutic for treating ovarian cancer by enhancing endoplasmic reticulum stress. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4813.

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Collier, Alexia B., Suryavathi Viswanadhapalli, Tae-Kyung Lee, Kara Kassees, Karla Parra, Gaurav Sharma, Tanner Reese et al. „Abstract 3986: Novel LIPA targeted therapy for treating ovarian cancer“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 3986. http://dx.doi.org/10.1158/1538-7445.am2023-3986.

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Abstract BACKGROUND: Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. Currently approved therapies have improved OCa survival for clinically localized disease, however, the majority (~90%) of patients with high-grade serous OCa (HGSOC) experience relapse with incurable metastases. There is a dire need for new therapeutic approaches. We hypothesized that the high basal endoplasmic reticulum stress (ERS) in OCa represents a critical and targetable vulnerability and may overcome the tumor heterogeneity. The objective of this project is to exploit increased ERS in ovarian cancer cells by engaging the novel target LIPA using the unique compound ERX-41. METHODS: The utility of ERX-41 as a new therapy was evaluated using MTT and CellTiter-Glo Cell Viability Assays. We used multiple established and patient derived OCa cell lines. The effect of ERX-41 on the Cell viability of patient-derived organoids (PDO) was measured using CellTiter-Glo 3D Assay. Long term effects of ERX-41 on cell survival were measured using colony formation assays. Apoptosis was measured using Annexin V and Caspase-Glo® 3/7 Assays. Cell cycle analysis was analyzed by Flow Cytometry. Mechanistic studies were done using LIPA knockout (KO) cells, RT-qPCR, and western blotting. Status of LIPA in OCa was determined using TNMplot database. In vivo efficacy of ERX-41 was tested using both cell line derived (CDX) and patient derived (PDXs) xenografts. RESULTS: TNM plot results showed that LIPA is highly expressed in OCa tumors compared to normal tissues and LIPA expression correlated with clinical grade. Kaplan-Meier plotter analyses of TCGA data revealed that LIPA expression is negatively correlated with overall survival in OCa patients. MTT and CellTitre-Glo assay results showed that ERX-41 significantly reduced the cell viability of both established and primary OCa cells, and PDO’s with an IC50 of ~500nM. ERX-41 treatment also significantly reduced the cell survival, increased S-phase arrest, and promoted apoptosis of OCa cells. A time course study revealed a robust and consistent induction of ERS markers (CHOP and sXBP1) in OCa cells by ERX-41 within 4h. Western blotting analyses also confirmed increased expression of ERS markers including CHOP, elF2α, PERK, and ATF4 upon ERX-41 treatment confirming that ERX-41 induces ERS. In xenograft studies, ERX-41 treatment resulted in ~66% reduction of tumor volume measured by Xenogen-IVIS. Further, in studies using PDX tumors, treatment with ERX-41 resulted in a significant reduction (~60%) of tumor volume and tumor weight. CONCLUSION: Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of action and implicate ERX-41 binding to LIPA induces ER stress, and apoptosis of OCa cells. Further molecular characterization of how ERX-41 binding to LIPA induces ER stress in OCa cells is ongoing. Citation Format: Alexia B. Collier, Suryavathi Viswanadhapalli, Tae-Kyung Lee, Kara Kassees, Karla Parra, Gaurav Sharma, Tanner Reese, Michael Hsieh, Xihui Liu, Xue Yang, Behnam Ebrahimi, Uday P. Pratap, Rahul Gopalam, Chia Yuan Chen, Scott Terry Elmore, Gangadhara Reddy Sareddy, Edward R. Kost, Jung-Mo Ahn, Ganesh V. Raj, Ratna K. Vadlamudi. Novel LIPA targeted therapy for treating ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3986.

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Viswanadhapalli, Suryavathi, Tae-Kyung Lee, Scott Elmore, Gaurav Sharma, Rahul Gopalam, Karla Parra, Tanner Reese et al. „Abstract 394: Preclinical evaluation of ERX-208, a potent inducer of ER stress for the treatment of ovarian cancer“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 394. http://dx.doi.org/10.1158/1538-7445.am2024-394.

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Abstract Background: Ovarian cancer (OCa) is the deadliest kind of gynecologic cancer in the United States. The long-term survival rate for OCa is less than 20% after five years. Intra-tumoral and inter-tumoral heterogeneity is implicated in tumor resistance to conventional therapies and the unsatisfactory clinical outcomes. Addressing these issues necessitates innovative therapies that target intrinsic common vulnerabilities within OCa. Recent studies have highlighted that high basal level of endoplasmic reticulum stress (ERS) in OCa as a critical vulnerability. We have identified a promising compound, ERX-208 that potently induces ERS in cancer cells. The objective of this study is to characterize the mechanisms and activity of ERX-208 using preclinical models. Methods: The biological activity of ERX-208 was examined across 17 distinct OCa cells, representing 5 diverse OCa subtypes. Mechanistic studies utilized Western blotting, immunohistochemistry (IHC), RNA-Seq analysis, and CRISPR/Cas9 knockouts (KO). Pharmacokinetics (PK) and toxicity studies were performed on C57BL/6 mice. Comprehensive preclinical assessments were carried out through cell line-derived xenografts (CDXs), patient-derived xenografts (PDXs), organoids (PDOs) and explants (PDEs). Results: ERX-208 demonstrated an IC50 of approximately 50-100 nM inducing ERS and reducing cell viability in OCa cells. Conversely, normal ovarian surface epithelial cells exhibited minimal effects from ERX-208. In vitro experiments revealed strong ERX-208-induced apoptosis in OCa cell lines. Mechanistic studies employing RNA sequencing, Western blotting, and RT-qPCR, confirmed activation of ERS pathways observed as early as 5 hours post-ERX-208 treatment. Our studies identified LIPA as a potential target, and KO of LIPA significantly diminished ERX-208 activity. Moreover, LIPA KO substantially impeded in vivo OCa tumor growth. ERX-208 up to a dose of 25 mg/kg showed no observable organ toxicity and had no effect on the mice's body weight. Dose range studies identified 10 mg/kg intraperitoneal as the minimal effective dose, achieving more than 50% tumor reduction. In preclinical models, ERX-208 inhibited the growth of OCa CDXs, PDXs, and ex vivo PDEs and PDO’s. IHC analyses indicated reduced proliferation (Ki-67) and increased activation of ERS markers, such as GRP78 and p-PERK. Conclusions: Collectively, our findings underscore the preclinical promise of ERX-208 as a potential therapeutic agent for treating OCa. Conflict: The patents surrounding ERX-208 are licensed to EtiraRx. Citation Format: Suryavathi Viswanadhapalli, Tae-Kyung Lee, Scott Elmore, Gaurav Sharma, Rahul Gopalam, Karla Parra, Tanner Reese, Michael Hsieh, Uday P. Pratap, Xue Yang, Behnam Ebrahimi, Henry Neal, Chia-Yuan Chen, Kara Kassees, Christian Cervantes, Zhenming Xu, Edward Kost, Gangadhara Reddy Sareddy, Rajeshwar R. Tekmal, Jung-Mo Ahn, Ganesh V. Raj, Ratna K. Vadlamudi. Preclinical evaluation of ERX-208, a potent inducer of ER stress for the treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 394.

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Collier, Alexia B., Suryavathi Viswanadhapalli, Rahul Gopalam, Tae-Kyung Lee, Kara Kassees, Karla Parra, Gaurav Sharma et al. „Novel LIPA-Targeted Therapy for Treating Ovarian Cancer“. Cancers 16, Nr. 3 (24.01.2024): 500. http://dx.doi.org/10.3390/cancers16030500.

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Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.

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Fuentes, Zenaida, Rahul Gopalam, Bianca A. Romo, Khaled Mohamed Nassar, Xue Yang, Behnam Ebrahimi, Paulina Ramirez et al. „Abstract 2100: Novel LIPA targeted therapy for treating inflammatory breast cancer“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 2100. http://dx.doi.org/10.1158/1538-7445.am2024-2100.

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Abstract Background: Inflammatory breast cancer (IBC) is a rare but incredibly aggressive subtype of breast cancer (BC). IBC accounts for 2-4% of all occurrences of breast cancer and results in 7-10% of breast cancer-related deaths. IBC is only partially treatable with current therapies such as chemotherapy, surgery, and radiotherapy. Identification of novel therapeutic targets is urgently required. The main organelle for the synthesis, folding, and modification of proteins is called the endoplasmic reticulum (ER). Since elevated basal ER stress (ERS) is usually found in many cancers including IBC, our hypothesis was that the high basal ERS in IBC constitutes a serious vulnerability that can be targeted. Recently, we developed a small molecule ERX41 that promotes ER stress by blocking Lysosomal acid lipase A (LIPA) function in ER of cancer cells. The goal of the project is to test the utility of ERX-41 in treating IBC. Methods: To study the effect of ERX-41, we have used three well-established IBC model cells. We evaluated the efficacy of ERX-41 as a novel therapeutic for treating IBC using cell viability assays. The long-term effects of ERX-41 on IBC cell survival were evaluated using colony formation assays. Annexin V assays were used to measure apoptosis. Reporter assays, splicing assays, RT-qPCR, and Western blotting were used in mechanistic investigations. The effectiveness of ERX-41 was examined in vivo using KPL4 cell-based xenografts. Results: ERX-41 significantly decreased the viability of all three IBC model cells (SUM149, SUM190PT, and KPL4), with an IC50 of about 125 nM in MTT assay. Additionally, ERX-41 treatment significantly decreased IBC cells capacity to form colonies and promoted apoptosis. Specificity of the ERX41 mediated actions were confirmed using LIPA KO cells. Using RTqPCR based splicing assays, we demonstrated increased splicing of XBP1 as early as 6 hours after ERX41 treatment. Western analyses showed robust induction of stress markers (CHOP, PERK, ATF4) in IBC cells upon treatment with ERX-41. In KPL4 xenograft studies, ERX-41 showed significant reduction in the tumor volume. IHC analyses confirmed decreased proliferation marker and increased ER stress markers. Conclusions: Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of action and implicate ERX-41 binding to LIPA induces ER stress and promotes apoptosis of IBC cells. Citation Format: Zenaida Fuentes, Rahul Gopalam, Bianca A. Romo, Khaled Mohamed Nassar, Xue Yang, Behnam Ebrahimi, Paulina Ramirez, Chia-Yuan Chen, Scott Elmore, Harika Nagandla, Uday Pratap, Christoforos Thomas, Suryavathi Viswanadhapalli, Jung-Mo Ahn, Ganesh Raj, Ratna K. Vadlamudi. Novel LIPA targeted therapy for treating inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2100.

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Viswanadhapalli, Suryavathi, Karla Parra, Tae-Kyung Lee, Rahul Gopalam, Kara Kassees, Tanner Reese, Gaurav Sharma et al. „Abstract PO3-26-11: Enhancing endoplasmic reticulum stress for treating endocrine therapy resistant breast cancers driven by mutant estrogen receptors“. Cancer Research 84, Nr. 9_Supplement (02.05.2024): PO3–26–11—PO3–26–11. http://dx.doi.org/10.1158/1538-7445.sabcs23-po3-26-11.

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Abstract Background: Estrogen receptor alpha (ERα) mutations are common (30-40%) in metastatic endocrine therapy-resistant breast cancers (ETR-BC), enable resistance to endocrine therapies and are the molecular drivers of ETR-BC. We had previously shown that an oligobenzamide, ERX-41, could enhance endoplasmic reticulum stress in ETR-BCs driven by mutant (MT) ERα, resulting in cancer cell death in vitro and and in vivo. To enable clinical translation of ERX-41, we performed lead optimization, followed by preclinical and IND-enabling studies. Methods: Over 2000 oligo-benzamides were designed, synthesized and tested in multiple BC models including those that express WT-ERα (MCF7, and ZR75) and BC models with acquired resistance (MCF7-Tam, and MCF7-LTLT) and engineered models that express MT-ERα (MCF7-ERα-D538G, MCF7-ERα-Y537S, ZR75-ERα-D538G, ZR75-ERα-Y537S). For our lead compound, mechanistic validation studies were performed using CRISPR LIPA mutants, RT-qPCR and Western blotting. Explants, organoids, cell line-(CDX) and patient-derived (PDX) xenografts were used to test the ex vivo and in vivo effectiveness of our lead compound as a monotherapy and in combination with abemaciclib. Results: Testing of >2000 synthesized oligo-benzamides identified a lead compound, ERX-315, that had broad and potent activity (IC50 between 20-100 nM) against both WT and MT (mutant) ERα-driven BC cells in in vitro assays. CRISPR KO of LIPA (which encodes lysosomal acid lipase (LAL) in BC cells abrogated cytotoxic response to ERX-315, validating LIPA as the molecular target of ERX-315. Ultrastructural and molecular studies confirm that ERX-315 induces significant endoplasmic reticulum stress, leading to a shutdown of de novo protein synthesis and apoptotic cell death in BC. Importantly, ERX-315 does not induce endoplasmic reticulum stress or cell death in normal cells and is non-toxic in animal models. We have shown that this capacity of ERX-315 to induce endoplasmic reticulum stress is unique among drugs targeting ERα, including selective ERα modulators and degraders, such as GDC-0180, AZD-9496 and fulvestrant. ERX-315 has potent anti-proliferative activity against MT-ERα-driven BC, as seen in genetically modified cell lines both grown as monolayer or spheroids in vitro, patient derived explants (PDEs) ex vivo and cell line derived (CDX) and patient-derived (PDX) xenografts in vivo. The combination of ERX-315 and CDK4/6 inhibitor abemaciclib was synergistic in decreasing the proliferation of both endocrine therapy-sensitive and endocrine therapy-resistant BC cells, in vitro, in xenograft models in vivo, and in primary patient-derived explants ex vivo. We are currently optimizing both the synthesis of ERX-315 using GMP process for kilogram scale production and validated methods for pharmacokinetic studies. We have developed formulations for both intravenous and oral administration with favorable pharmacokinetic parameters and proven utility of the formulated ERX-315 against CDX and PDX tumors in vivo. Toxicity studies in dogs and rodents have demonstrated >8-fold therapeutic to toxicity window. A phase I clinical trial is planned to be open to enrollment by Q1 2024. Conclusions: We have identified a lead compound ERX-315, which represents a novel class of agent that induce catastrophic levels of ER stress resulting in cancer cell death and that can effectively work against multiple forms of ETR-BC, including those driven by MT-ERα. Preclinical studies, GMP manufacturing, formulation and IND-enabling studies are being completed in time for the commencement of the phase I clinical trial by Q1 2024. Citation Format: Suryavathi Viswanadhapalli, Karla Parra, Tae-Kyung Lee, Rahul Gopalam, Kara Kassees, Tanner Reese, Gaurav Sharma, Xihui Liu, Xue Yang, ChiaYuan Chen, Carlos Roggero, Liping Chen, Sautam Bhattacharya, Uday Pratap, Russell Hayward, Sharron Gargosky, Jung-Mo Ahn, Ganesh V. Raj, Ratna Vadlamudi. Enhancing endoplasmic reticulum stress for treating endocrine therapy resistant breast cancers driven by mutant estrogen receptors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-26-11.

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Devarakonda, S., und R. Govindan. „TRAC(ERx)-ing lung cancer evolution“. Annals of Oncology 28, Nr. 8 (August 2017): 1690–92. http://dx.doi.org/10.1093/annonc/mdx313.

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Nobrega, Rayssa Lourenna Trigueiro, Rony Lucas Silva Viana, Marianna Barros Silva, Luciana Duarte Martins Matta, Giulianna Paiva Viana Andrade Souza, Hugo Alexandre Oliveira Rocha und Raniere Fagundes Melo-Silveira. „Evaluation of the Pharmacological Activities of a Xylan from Corn Cobs“. Polysaccharides 6, Nr. 1 (01.02.2025): 9. https://doi.org/10.3390/polysaccharides6010009.

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Xylans, polysaccharides abundantly derived from agricultural byproducts, have shown potential pharmacological properties, making them a subject of increasing research interest. This study aimed to expand the understanding of xylans’ pharmacological properties and relate them to their composition. A method combining ultrasound and alkaline media for xylan extraction from corn cobs (ERX) was used, resulting in a significant increase in final yield compared to other methodologies. The physicochemical characterization of ERX was carried out, and its antioxidant, cytotoxic, anticoagulant, and immunomodulatory properties were evaluated. ERX demonstrated significant antioxidant activity with metal-chelating properties and induced apoptosis in HeLa tumor cells (p < 0.0001). It also reduced nitric oxide (NO) production by activated macrophages and extended the blood coagulation time, as assessed by the APTT assay (p < 0.0001). Further fractionation of ERX using various organic solvents resulted in multiple xylan subfractions. Among them, the ethanol-derived subfraction E1.4 exhibited remarkable pharmacological activities, including metal-chelation, cytotoxicity against HeLa cells via apoptosis, reduced NO production (p < 0.0001), and prolonged coagulation times (p < 0.0001). E1.4 is heteroxylan with a molecular weight of approximately 100 kDa. These findings suggest that corn cobs could be a promising source of pharmacologically significant molecules, particularly the heteroxylan E1.4. Future studies should focus on the structural characterization of this xylan to understand the relationship between structure and biological activity and explore the therapeutic potential of E1.4 in vivo models.

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SCHNEIDER, MARY ELLEN. „Clock Is Ticking Toward Medicare eRx Penalties“. Family Practice News 42, Nr. 9 (Mai 2012): 1–3. http://dx.doi.org/10.1016/s0300-7073(12)70382-1.

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Kim, Young-Ung. „ERX : A Generation Tool of XML Schema based on Entity-Relationship Model“. Journal of the Institute of Webcasting, Internet and Telecommunication 13, Nr. 2 (30.04.2013): 149–55. http://dx.doi.org/10.7236/jiibc.2013.13.2.149.

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Shugani, Mani, Mahendra Aynyas, Harsha Pawar und Sankar P. Sanyal. „First Principles Study of Structural and Electronic Properties of ErX (X=Cu, Ag and Au) Intermetallics“. Advanced Materials Research 1141 (August 2016): 77–83. http://dx.doi.org/10.4028/www.scientific.net/amr.1141.77.

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The electronic structures, densities of states and Fermi surfaces of ErX (X = Cu, Ag and Au) intermetallic compounds are studied using full potential linear augmented plane wave (FP-LAPW) method within generalized gradient approximation (GGA) for the exchange-correlation functional. The total energies are computed as a function of volume and fitted to the Birch equation of state. The ground state properties such as equilibrium lattice constants (a0), bulk modulus (B) and pressure derivative of bulk modulus (B') and density of states at the Fermi level N (EF) are calculated. The states at the Fermi level (EF) are dominated by Er ‘d’ states with significant contribution of ‘p’ and ‘d’ states of X. We have also plotted charge density and Fermi surface to study the bonding properties of ErX compounds.

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Alcantara, Marlon F., Yu Cao, Benyuan Liu, Chang Liu, Ning Zhang, Pengfei Zhang, Terry Griffin, Walter H. Curioso, Cesar Ugarte-Gil und Maria J. Brunette. „eRx – A technological advance to speed-up TB diagnostics“. Smart Health 16 (Mai 2020): 100117. http://dx.doi.org/10.1016/j.smhl.2020.100117.

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Zakaly, Hesham M. H., Antoaneta Ene, Oyeleke I. Olarinoye, Samir Y. Marzouk, Shams H. Abdel-Hafez, Mohamed S. Shams und Yasser S. Rammah. „Investigation of Er3+ Ions Reinforced Zinc-Phosphate Glasses for Ionizing Radiation Shielding Applications“. Materials 14, Nr. 22 (10.11.2021): 6769. http://dx.doi.org/10.3390/ma14226769.

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Melt quenching technique is used for preparing glasses with chemical formula (70P2O5)–(16 − x)CdO–(14ZnO)–(xEr2O3), (x = 1–6 mol%). These glasses were named Er1, Er2, Er3, Er4, Er5, and Er6, respectively. Photon buildup factors, fast neutron absorption, and electron stopping of the prepared glasses were examined. Glasses’ density was varied from 3.390 ± 0.003 for the Er1 glass sample to 3.412 ± 0.003 for the Er6 glass sample. The Buildup factor (BUF) spectra have relatively higher values in the Compton Scattering (CS) dominated areas compared to both Photoelectric effect (PE), and Pair Production (PP) dominated energy regions. The highest BUF appeared at the Er atom K-absorption edge, whose intensity increases as the molar concentration of Er2O3 in the glasses increases. The photon absorption efficiency (PAE) of the glasses increases according to the trend (PAE)Er1 < (PAE)Er2 < (PAE)Er3 < (PAE)Er4 < (PAE)Er5 < (PAE)Er6. Fast neutron removal cross-section, FNRC (ΣR) values of the glasses obtained via calculation varied from 0.1045–0.1039 cm−1 for Er1–Er6. Furthermore, the continuous slowing down approximation mode (CSDA) range enhances the kinetic energy of electrons for all glasses. Generally, results revealed that the investigated glasses could be applied for radiation shielding and dosimetric media.

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Curioso, Walter H., und Maria J. Brunette. „Inteligencia artificial e innovación para optimizar el proceso de diagnóstico de la tuberculosis“. Revista Peruana de Medicina Experimental y Salud Pública 37, Nr. 3 (24.09.2020): 554–8. http://dx.doi.org/10.17843/rpmesp.2020.373.5585.

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La tuberculosis sigue siendo un tema urgente en la agenda de la salud urbana, especialmente en países de medianos y bajos ingresos. Existe la necesidad de desarrollar e implementar soluciones innovadoras y efectivas en el proceso de diagnóstico de la tuberculosis. En este artículo, se describe la importancia de la inteligencia artificial como una estrategia para enfrentar la tuberculosis, mediante un diagnóstico oportuno. Además de los factores tecnológicos, se enfatiza el rol de los factores sociotécnicos, culturales y organizacionales. Se presenta como caso la herramienta eRx que involucra algoritmos de aprendizaje profundo y, en específico, el uso de redes neuronales convolucionales. eRx es una herramienta prometedora basada en inteligencia artificial para el diagnóstico de tuberculosis que comprende una variedad de técnicas innovadoras que implican el análisis remoto de rayos X para casos sospechosos de tuberculosis. Las innovaciones basadas en herramientas de inteligencia artificial pueden optimizar el proceso de diagnóstico de la tuberculosis y de otras enfermedades transmisibles.

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Ault, Alicia. „More Than Half Opted Out of PQRS and eRx Incentives“. Caring for the Ages 15, Nr. 8 (August 2014): 10. http://dx.doi.org/10.1016/j.carage.2014.07.009.

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SCHNEIDER, MARY ELLEN. „Act by June 30 to Avoid eRx Penalties for 2013“. Cardiology News 10, Nr. 6 (Juni 2012): 5. https://doi.org/10.1016/s1544-8800(12)70161-6.

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Daif, Mohamad Nagy. „When in a multiplicative derivation additive?“ International Journal of Mathematics and Mathematical Sciences 14, Nr. 3 (1991): 615–18. http://dx.doi.org/10.1155/s0161171291000844.

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Our main objective in this note is to prove the following. SupposeRis a ring having an idempotent elemente(e≠0, e≠1)which satisfies:(M1) xR=0 implies x=0.(M2) eRx=0 implies x=0 (and hence Rx=0 implies x=0).(M3) exeR(1−e)=0 implies exe=0.Ifdis any multiplicative derivation ofR, thendis additive.

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Johnson, David A. „PQRI, VBP, ACO, eRx, MoC …: Understanding the Lexicon of Health-Care-Reform Legislation“. American Journal of Gastroenterology 106, Nr. 9 (September 2011): 1570–74. http://dx.doi.org/10.1038/ajg.2011.289.

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NAKANO, Tatsuya, Yuya KAMBE und Toshiaki MIYAUCHI. „Development of New Heat Resistant Acrylic Rubber (Denka ER^® ERX-219)“. NIPPON GOMU KYOKAISHI 93, Nr. 8 (2020): 269–72. http://dx.doi.org/10.2324/gomu.93.269.

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Reknimitr, R., S. Sherman, E. Fogel, J. Fitzgerald, J. Croffie und G. Lehman. „Sphincter of Oddi dysfunction (SOD) in children: frequency and results of endoscopic therapy (ERx)“. American Journal of Gastroenterology 95, Nr. 9 (September 2000): 2485. http://dx.doi.org/10.1111/j.1572-0241.2000.02612.x.

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Xiao, Nan, Supriya Mahajan, Rajiv Kishore, Vishwanath Muthyam Venkata, Nishath Ahmed Shaik, Edwin J. Anand und Ranjit Singh. „Successful Implementation of eRx Systems: Creating Technology–Organization Alignment using the Strategy-Map Approach“. Information Systems Management 31, Nr. 2 (03.04.2014): 104–19. http://dx.doi.org/10.1080/10580530.2014.890427.

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Martinez, Julian A., und Colin J. Barnstable. „Erx, a Novel Retina-Specific Homeodomain Transcription Factor, Can Interact with Ret 1/PCEI Sites“. Biochemical and Biophysical Research Communications 250, Nr. 1 (September 1998): 175–80. http://dx.doi.org/10.1006/bbrc.1998.9261.

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Kelava Ugarković, Nikolina, Miljenko Konjačić, Zvonimir Prpić, Kristijan Tomljanović und Damir Ugarković. „Effect of Sex and Age on Nutritional Content in Wild Axis Deer (Axis axis Erx.) Meat“. Animals 10, Nr. 9 (02.09.2020): 1560. http://dx.doi.org/10.3390/ani10091560.

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The aim of this study is to examine the effect of sex and age on proximate chemical, fatty acid, amino acid and mineral content of axis deer (Axis axis Erx.) meat. Sixteen (n = 16) animals were hunt-harvested and assigned to groups according sex and age (sub-adult and adult). All analyses were made on m. longissimus thoracis sampled between the 9th and 13th ribs. Minor differences in nutritional composition of axis deer meat were found between analysed sex and age groups. Axis deer meat has a high protein (22.8%) and low fat (1.39%) content. Saturated fatty acids accounted for 44.97% and polyunsaturated for 29.66% of the total fatty acids. Ratios of fatty acids were within the recommended values. Glutamic and aspartic acid were the most abundant non-essential, and lysine and leucine the most common essential amino acids. The ratio of essential to non-essential amino acids was <1. Potassium and phosphorous were the dominant macro-minerals, while iron and zinc were the dominant micro-minerals. The results of this study show that regardless of sex or age, axis deer meat can be considered a good source of basic macro- and micro-nutrients, and can be recommended as a substitute for red meat from domestic animals.

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Krut’ko, V. A., M. G. Komova, D. V. Pominova, A. V. Popov, A. B. Yaroslavtsev, G. E. Nikiforova und A. V. Gavrikov. „Synthesis and Spectral Properties of La1 – xBWO6:Erx and La1 – x – yBWO6:Ybx,Ery Upconversion Phosphors“. Inorganic Materials 59, Nr. 9 (September 2023): 982–94. http://dx.doi.org/10.1134/s002016852309008x.

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El Hassani, Hicham, Said Benkachcha und Jamal Benhra. „New Genetic Operator (Jump Crossover) for the Traveling Salesman Problem“. International Journal of Applied Metaheuristic Computing 6, Nr. 2 (April 2015): 33–44. http://dx.doi.org/10.4018/ijamc.2015040103.

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Inspired by nature, genetic algorithms (GA) are among the greatest meta-heuristics optimization methods that have proved their effectiveness to conventional NP-hard problems, especially the traveling salesman problem (TSP) which is one of the most studied supply chain management problems. This paper proposes a new crossover operator called Jump Crossover (JMPX) for solving the travelling salesmen problem using a genetic algorithm (GA) for near-optimal solutions, to conclude on its efficiency compared to solutions quality given by other conventional operators to the same problem, namely, Partially matched crossover (PMX), Edge recombination Crossover (ERX) and r-opt heuristic with consideration of computational overload. The authors adopt a low mutation rate to isolate the search space exploration ability of each crossover. The experimental results show that in most cases JMPX can remarkably improve the solution quality of the GA compared to the two existing classic crossover approaches and the r-opt heuristic.

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Rasul, Muhammad Nasir, Memoona Mehmood, Altaf Hussain, Alina Manzoor, Muhammad Azhar Khan und Faisal Iqbal. „Ab-initio investigation of structural, electronic, magnetic and thermodynamic properties of ErX (X = N, P, As and Sb) compounds“. Computational Condensed Matter 27 (Juni 2021): e00540. http://dx.doi.org/10.1016/j.cocom.2021.e00540.

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Tripathi, S. N., Vipul Srivastava, Rabah Khenata und S. P. Sanyal. „Electronic band structure, mechanical and thermodynamic properties of Erbium chalcogenides ErX (X = S, Se and Te): A computational insight“. Computational Condensed Matter 28 (September 2021): e00563. http://dx.doi.org/10.1016/j.cocom.2021.e00563.

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Pohlmeyer, K., und S. Ueberschär. „Der Fang von Steinmardern (Martes foina Erx.) mit der Rasenfalle unter den Aspekten des Tierund Artenschutzes sowie der Sicherheit“. Zeitschrift für Jagdwissenschaft 46, Nr. 3 (September 2000): 167–75. http://dx.doi.org/10.1007/bf02241354.

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Goodman, S. A., F. D. Auret, F. K. Koschnick, J. M. Spaeth, B. Beaumont und P. Gibart. „Electrical Characterization of Defects Introduced In n-GaN During High Energy Proton and He-Ion Irradiation“. MRS Internet Journal of Nitride Semiconductor Research 4, S1 (1999): 606–11. http://dx.doi.org/10.1557/s1092578300003124.

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We report on the electrical properties of defects as determined by deep level transient spectroscopy (DLTS) introduced in epitaxially grown n-GaN by 2.0 MeV protons and 5.4 MeV He-ions. After He-ion bombardment three electron traps ER3 (Ec − 0.196 eV), ER4 (Ec − 0.78 eV), and ER5 (Ec − 0.95 eV) were introduced uniformly in the region profiled by DLTS with introduction rates of 3270 ± 200, 1510 ± 300, and 3030 ± 500 cm−1 respectively. Capture cross section measurements revealed that the electron capture kinetics of ER5 is similar to that of a line defect. A defect with similar electronic properties as ER3 is observed after 2.0 MeV proton irradiation. The emission rate of ER3 depends on the electric field strength in the space-charge region. This emission rate is modelled according to the Poole-Frenkel distortion of a square well with a radius of 20 ± 2 Å or alternatively, a Gaussian well with a characteristic width of 6.0 ± 1 Å. Hence, we conclude that ER1 is a point defect which appears to have an acceptor like character. Two additional electron traps, ER1 (Ec −0.13 eV) and ER2 (Ec − 0.16eV) with introduction rates of 30 ± 10 and 600 ± 100 cm−1 not thusfar observed after electron or He-ion bombardment were observed after proton irradiation.

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Kampa, Marilena, George Notas, Vassiliki Pelekanou, Maria Troullinaki, Maria Andrianaki, Kalliopi Azariadis, Errika Kampouri, Katerina Lavrentaki und Elias Castanas. „Early membrane initiated transcriptional effects of estrogens in breast cancer cells: First pharmacological evidence for a novel membrane estrogen receptor element (ERx)“. Steroids 77, Nr. 10 (August 2012): 959–67. http://dx.doi.org/10.1016/j.steroids.2012.02.011.

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Parrish, Richard H., Lucy Gilak, Donna Bohannon, Steven P. Emrick, Brian Serumaga und Roy Guharoy. „Minimizing Medication Errors from Electronic Prescription Transmission—Digitizing Compounded Drug Preparations“. Pharmacy 7, Nr. 4 (07.11.2019): 149. http://dx.doi.org/10.3390/pharmacy7040149.

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Lack of standardization related to compounded drug preparations, especially in the transition of care situations, threatens patient safety by facilitating medication error. This paper outlines progress to-date from the United States Pharmacopeia (USP) Expert Panel on the Exchange of Compounded Drug Preparation Information in Health IT Systems. The work plan developed for the group is focused on proposing a set of encoding rules that would govern how compounded nonsterile drug preparations (CNSPs) are digitized and exchanged, including patient electronic health records (EHR), pharmacy systems, e-prescribing (eRx), and other Health IT (HIT) systems to ensure a seamless compounding process tailored to the needs of an individual patient. Included in this work are identifying authorized compounding monographs, surveying provider and end-user groups for information about data specificity during e-prescribing, and generating guidelines for the development of a compatible data model for clinical formulation identifiers (CF-IDs). This paper will also discuss how evolving nomenclature standards for CNSPs within HIT systems are part of a quality assurance system for comprehensive medication management (CMM) in children, thereby minimizing medication errors across the continuum of care. Finally, a network approach for the design of medication management systems for children and their families/caregivers is proposed.

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Ardiyarta, Bayu, Joko Prihantono, Dikdik S. Mulyadi und Tasdik Mustika Alam. „Sebaran dan Estimasi Ketebalan Sedimen Permukaan Dasar Laut Berdasarkan Nilai Koefisien Refleksi Sub Bottom Profiler (Studi Kasus Perairan Utara Serang, Banten)“. Jurnal Chart Datum 4, Nr. 2 (28.12.2018): 107–16. http://dx.doi.org/10.37875/chartdatum.v4i2.132.

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Peningkatan aktivitas di bidang reklamasi pesisir berupa penambangan pasir dan mineral, operasi pengerukan (dredging) serta pembangunan sarana pemukiman diwilayah pesisir membutuhkan peta-peta dasar laut yang akurat. Sub Bottom Profiler (SBP) merupakan salah satu instrument akustik bawah air yang mempunyai frekuensi yang rendah, sehingga mampu menggambarkan lapisan sedimen dibawah dasar laut. Informasi jenis sedimen dasar laut dapat dilakukan dengan menggunakan metode akustik bawah laut termasuk dengan menggunakan SBP. Keunggulan SBP dibandingkan instrument akustik bawah air lainnya adalah dapat digunakan untuk mengestimasi ketebalan sedimen permukaan tersebut. Pada penelitian ini telah dilakukan klasifikasi sedimen permukaan dasar laut di perairan utara Kabupaten Banten dengan cara menghitung nilai koefisien refleksi data SBP dengan membandingkan energi pantulan (ERx) dengan energi yang dipancarkan (ETx) yang kemudian dikalibrasi dengan data sampling sedimen yang juga diambil pada saat survei dilakukan. Sedangkan ketebalan sedimen permukaan dilakukan dengan melakukan picking horizon di penampang SBP antara lapisan dasar laut dengan reflector yang pertama. Selisih antara dua reflector tersebut merupakan nilai ketebalan. Area survei adalah perairan utara kabupaten Serang Banten karena lokasi ini merupakan area penambangan pasir, sehingga memiliki jenis sedimen yang homogen. Hasil dari penelitian ini adalah nilai koefisien refleksi dengan rata-rata 0.3076 sampai dengan 0.4501 yang kemudian diklasifikasikan sesuai dengan tabel Hamilton 1982 pasir kasar, pasir halus, pasir sangat halus dan pasir lembut. Nilai ketebalan sedimen berkisar antara 0 sampai dengan 6.3 meter dengan rata-rata 1.47 meter.

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Ugarte-Gil, Cesar, Maria Icochea, Juan Carlos Llontop Otero, Katerine Villaizan, Nicola Young, Yu Cao, Benyuan Liu, Terence Griffin und Maria J. Brunette. „Implementing a socio-technical system for computer-aided tuberculosis diagnosis in Peru: A field trial among health professionals in resource-constraint settings“. Health Informatics Journal 26, Nr. 4 (18.07.2020): 2762–75. http://dx.doi.org/10.1177/1460458220938535.

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A major challenge of tuberculosis diagnosis is the lack of universal accessibility to bacteriological confirmation. Computer-aided diagnostic interventions have been developed to address this gap and their successful implementation depends on many health systems factors. A socio-technical system to implement a computer-aided diagnostic tuberculosis diagnosis was preliminary tested in five primary health centers located in Lima, Peru. We recruited nurses (n = 7) and tuberculosis physicians (n = 5) from these health centers to participate in a field trial of an mHealth tool (eRx X-ray diagnostic app). From September 2018 to February 2019, the nurses uploaded images of chest X-rays using smartphones and the physicians reviewed those images on web-based platforms using tablets. Both completed weekly written feedback about their experience. Each nurse participated for a median duration of 12 weeks (interquartile range = 7.5–15.5), but image upload was only possible at a median of 58 percent (interquartile range = 35.1%–84.4%) of those weeks. Each physician participated for a median duration of 17 weeks (interquartile range = 12–17), but X-ray image review was only possible at a median of 52 percent (interquartile range = 49.7%–57.4%) of those weeks. Heavy workload was most frequently provided as the reason for missing data. Several infrastructural and technological challenges impaired the effective implementation of the mHealth tool, irrespective of its diagnostic accuracy.

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Olawale Kolapo Steve Emiola, Musibau Abayomi Omoloye und Anietie Edem Udokang. „Statistical analysis on bio-efficacy of different solvent fraction of Andrographis paniculata against some bacteria“. World Journal of Advanced Research and Reviews 12, Nr. 1 (30.10.2021): 473–80. http://dx.doi.org/10.30574/wjarr.2021.12.1.0546.

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Andrographis paniculata leaves on bacterial that cause diseases. And it was aimed to compare the effect of Andrographis paniculata on some selected bacteria with the normal antibiotics. The bacterial isolates used in the study were Staphylococcuc aurcus, Streptococcus pyogens, Proteus vulgaris and Escherichia coli. The data was collected by experimental method from laboratory as source of primary data. Randomized complete block design with two-way analysis of variance were used to analyze the data in order to determine the significant difference in efficacy of fractions solvent extract of Andrographis paniculata leaves on bacteria. The normal antibiotics used are: Streptomycin, Gentamycin, Amoxillin, Chloramphenicol, Contrimoxazole, ofloxaacin, Erthrommycin, ERX, PT and Ceftriaxone. MINITAB 16 statistical software were used for computation analysis of the data collected. The result of the analysis reveal that there is significant difference in the efficacy of different antibiotics on bacteria that cause diseases. Although it was observed that the level of inhibition of each antibiotics were not the same but they all possess antibicteria properties that could be used to treat some bacteria diseases. Therefore, it was concluded that Andrographis paniculata is highly potent in the treatment of some selected bacterial diseases. I hereby recommended that, the effective drugs could be produced from Andrographis paniculata leaves used in traditional medicine, thereby enhance self-reliance, more active drugs can be produced to solve the present-day problems of drug resistance in the health management.

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Eslami, Majid, Mohammad Memarian und Bahman Yousefi. „ERX-41; Promising compound by targeting LIPA is a new Achilles heel therapeutic strategy for hard-to-treat solid tumors by induction of endoplasmic reticulum stress“. Vacunas (English Edition) 24, Nr. 4 (Oktober 2023): 348–57. http://dx.doi.org/10.1016/j.vacune.2023.10.009.

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Kim, Yisik, Jei Keon Chae, Ji Young Yoon, Soo Kyeong Song, Lae Young Jung, Sun Hwa Lee, Sang Rok Lee, Kyoung Seok Lee und Jae Ki Ko. „A RANDOMIZED COMPARISON OF SECOND-GENERATION ZOTAROLIMUS-ELUTING RESOLUTE STENTS VERSUS EVEROLIMUS-ELUTING XIENCE V STENTS IN REAL-WORLD PATIENTS: 4-YEAR LONG-TERM CLINICAL OUTCOMES OF LISA-ERX TRIAL“. Journal of the American College of Cardiology 65, Nr. 10 (März 2015): A51. http://dx.doi.org/10.1016/s0735-1097(15)60051-1.

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Migdady, Yazan, Mohammed Salhab und Adam J. Olszewski. „Living In Remission: Disparities In Conditional Survival Among Non-Hodgkin Lymphoma Survivors“. Blood 122, Nr. 21 (15.11.2013): 2915. http://dx.doi.org/10.1182/blood.v122.21.2915.2915.

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Abstract Introduction With advances in therapy, the numbers of survivors of aggressive and indolent non-Hodgkin lymphomas (NHL) are increasing. Conventional prognostic scores such as the International Prognostic Index (IPI) provide survival predictions at diagnosis, but it is not known whether factors such as stage, age, sex and race retain prognostic value for patients who successfully complete initial treatment and live in remission or under watchful waiting. In order to inform surveillance and survivorship care strategies, we studied conditional survival (CS), which describes outcomes in patients who survive a pre-specified time since diagnosis. Using the population-based, Surveillance, Epidemiology, and End Results (SEER) registry we identified factors that influence initial and long-term disparities in NHL. Methods We analyzed SEER data on 157,846 adults diagnosed between 1998 and 2010 with Burkitt's (BL), diffuse large B-cell (DLBCL), peripheral T-cell (PTCL), mantle cell (MCL), follicular (FL) or small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). We calculated 5-year relative survival conditional on remaining alive beyond the initial 1 to 4 years from the diagnosis. Age-standardized CS estimates were used to compare the NHL subtypes. We then calculated absolute (excess risk, ER), relative (relative risk) and summary measures of disparity for groups defined by stage (I/II versus III/IV), age (< or ≥ 60 years), sex and race ‒ at diagnosis (ER0) and after 1 to 4 years (ER1-ER4) for each subtype. Differences in trends were evaluated by interaction test of slope inequality (PΔ). Results The 5-year relative survival at diagnosis ranged from 32% in PTCL to 81% in FL (see Figure). In BL and DLBCL, CS notably improved after the first year, nullifying the difference between them (ER0 20%, ER1 1%). After 2 years, further prognosis was as good for BL/DLBCL as for FL (CS ∼85%), but remained significantly worse in PTCL. In “indolent” NHLs the CS remained relatively flat and MCL demonstrated the worst prognosis of all subtypes after 2 years. Among aggressive NHLs, the disparities in BL and DLBCL evolved differently than in PTCL. The initial prognostic significance of advanced stage subsided within 2 years in BL (ER0 24%, ER2 4%, PΔ=.0002) and DLBCL (ER0 20%, ER2 5%, PΔ=.0005), but persisted in PTCL (ER0 28%, ER2 19%; PΔ=.12). Likewise, the disparity between patients < or ≥ 60 years old significantly decreased in BL (ER0 22%, ER2 8%, PΔ=.0003) and DLBCL (ER0 18%, ER2 7%, PΔ=.005), but not in PTCL (ER0 17%, ER2 13%, PΔ=.78). The initial disparity in black patients, compared to white, largely decreased in all three subtypes (ER0 13% in BL, 7% in DLBCL and 8% in PTCL, ER2 7%, 1% and 1%, respectively). In MCL, FL and SLL, patients with advanced stage had continuously worse CS (ER0/ER2=15%/10%, 13%/8%, 7%/10%, respectively). In CLL outcomes were equal to stage I/II rather than stage IV SLL. The difference between age groups also essentially carried on (ER0/ER2=22%/16%, 11%/7%, 15%/11%, respectively in MCL, FL and SLL, all PΔ>0.2). The extent of disparity between the age groups was particularly large in MCL (ER2-4>42% between groups<40 and ≥80 years, compared with ER2-4=11-28% in all other NHLs). In SLL/CLL, the CS in black patients was persistently worse than in other racial groups (ER0-4>12% compared with whites). Conversely, in MCL it steadily improved (from ER0 -0.6% to ER4 -12% compared with whites) and was higher than in other races after the first year. Gender disparities were small at diagnosis (ER0= 0-4%) and without evident trends in any NHL. Conclusions In patients surviving just the first year from NHL diagnosis, further prognosis markedly improves in BL and DLBCL, underscoring their high curability. PTCL and MCL follow a different trajectory and have a worse outlook than BL/DLBCL in survivors. Age and stage, major components of the IPI, lose much of their initial prognostic value after the first year in BL and DLBCL, but not in PTCL. Conversely, age, race and stage continue to significantly affect disease-related mortality in indolent NHL. The surprisingly favorable survival in black patients with MCL and their persistently poorer outcomes in SLL/CLL suggest biological differences rather than issues related to access to treatment. Counseling NHL survivors on their prognosis and planning long-term surveillance should take these factors into consideration. Disclosures: No relevant conflicts of interest to declare.

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Fondevilla, Sara, Mª José González-Bernal, Noura Omri Ben Youssef und Diego Rubiales. „Development of Quantitative Real-Time PCR Assays to Quantify Erysiphe pisi and Erysiphe trifolii and Its Implementation for Monitoring Their Relative Prevalence in Pea Crops in Spain and Tunisia“. Agronomy 12, Nr. 2 (28.01.2022): 334. http://dx.doi.org/10.3390/agronomy12020334.

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E. pisi was thought to be the only causal agent of powdery mildew in peas, with three genes, er1, er2 and Er3, conferring resistance to this pathogen. Recently, E. trifolii has also been found to cause this disease in peas in different countries, but its relevance in pea powdery mildew disease worldwide is unknown. The objective of this study was to develop a method to identify and quantify E. pisi and E. trifolii and use it to analyze the relative prevalence of E. pisi and E. trifolii in pea fields in Spain and Tunisia. We also wanted to discern the effect of the er1, er2 and Er3 resistance genes on the relative amount of E. pisi/E. trifolii. Using the polymorphic sites present between E. pisi and E. trifolii ITS sequences, we developed a qPCR method capable of identifying and quantifying these pathogens. Our results revealed, for the first time, the occurrence of E. trifolii in Tunisia and that the presence of er1, er2 and Er3 genes have a clear effect on the ratio E. pisi/E. trifolii in both countries.

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Fondevilla, S., C. Chattopadhyay, N. Khare und D. Rubiales. „Erysiphe trifolii is able to overcome er1 and Er3, but not er2, resistance genes in pea“. European Journal of Plant Pathology 136, Nr. 3 (08.03.2013): 557–63. http://dx.doi.org/10.1007/s10658-013-0187-6.

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Zheng, Xueling, Chunyu Zhou, Ruidong Zhang, Chao Gao, Jingdong Han, Tianyou Wang und Huyong Zheng. „A Study on Heterogeneity and Early Response to Chemotherapy in Pediatric ETV6-RUNX1 Positive Acute Lymphoblastic Leukemia By RNA-Seq Expression Profile“. Blood 142, Supplement 1 (28.11.2023): 6060. http://dx.doi.org/10.1182/blood-2023-184389.

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Objective ETV6-RUNX1 positive ALL is the most common type in childhood acute lymphoblastic leukemia(ALL), and it is also a type with good prognosis. However, there are still recurrent or refractory cases in this type, and there is still heterogeneity among individuals.In this research, we investigate the heterogeneity of ETV6-RUNX1 positive ALL in children by RNA-seq expression profile, and to explore the early response to chemotherapy and microenvironment characteristics of different clusters, so as to provide evidences for the exploration of genetic high-risk factors and clinical personalized diagnosis and treatment of such children. Method From September 2019 to June 2021, 72 children with newly diagnosed ETV6-RUNX1 positive ALL in standard risk group were enrolled and treated with CCLG-ALL-2018 chemotherapy protocol, which were all detected by RNA-seq technology. The sequencing results were analyzed by cluster analysis and bioinformatics analysis. We explored the early response to chemotherapy and microenvironment characteristics of the different clusters. Result ETV6-RUNX1 positive ALL were divided into three groups according to the RNA-seq expression profile including 16 cases (22.2%) in ER1 group, 35 cases (48.6%) in ER2 group and 21 cases (29.2%) in ER3 group. The number of patients with co-negative minimal residual disease (MRD) by flow cytometry (MRD-FCM) and next-generation sequencing (MRD-Gene) on the 15th day of chemotherapy in ER1 and ER3 groups was significantly different (3/16 vs. 13/21, P=0.0178), while there were 17 cases (17/35) with co-negative MRD in ER2 group after fifteen-day chemotherapy. It showed that the proportion of NK cells ( P=0.056) and CD8 + T cells ( P=0.047) in peripheral blood in ER1 group were both higher than those in ER3 group. Compared with ER3 group, ER1 group showed low expression of RPL41 and high expression of MRPS28 and SERPIND1, which were mainly involved in stress, proliferation and drug resistance of cells and the differentiation of hematopoietic stem cell. In addition, ER1 group showed lower expression of ribosome-related genes and higher activation of mTOR pathway than ER3 group. Conclusion The heterogeneity in gene expression profile were presented in children with ETV6-RUNX1 positive ALL. Compared with ER3 group, patients in ER1 group may have a poorer early response to chemotherapy with a relatively higher risk due to the stronger proliferation and drug resistance of leukemic cells probably. For patients in ER1 group, even if MRD is negative on the 15th day of themotherapy, it may be necessary to strengthen the observation of early response and consider the treatment for escalated risk in time.

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Ramli, Mutiara M., Geertruida M. Sipahelut und Gemini E. Malelak. „Pengaruh Pemberian Ekstrak Rosela (Hibiscus sabdariffa Linn) dengan Metode Evaporasi Terhadap Kualitas Kimia dan Organoleptik Daging Se'i Kambing.docx“. Animal Agricultura 1, Nr. 3 (29.02.2024): 203–13. http://dx.doi.org/10.59891/animacultura.v1i3.37.

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Daging adalah bagian dari hewan potong sebagai bahan makanan, selain mempunyai penampakan yang menarik selera juga merupakan sumber protein hewani berkualitas tinggi. Penelitian ini telah dilakukan dengan tujuan untuk mengetahui pengaruh pemberian ekstrak rosela (Hibiscus Sabdariffa) terhadap kualitas daging se’i kambing. Metode yang digunakan adalah metode percobaan dengan Rancangan Acak Lengkap (RAL) yang terdiri dari 4 perlakuan dan 4 ulangan sehingga terdapat 16 unit percobaan. Pemberian ekstrak rosela terdiri dari perlakuan ER0=0%, ER1=1%, ER2=3%, ER3=5%. Parameter yang diukur dalam penelitian adalah uji fisikokimia meliputi kadar protein, kadar lemak, kadar kolesterol, aktivitas antioksidan dan uji organoleptik meliputi warna, aroma dan rasa. Hasil uji statistik menunjukkan bahwa pemberian ekstrak bunga rosela berpengaruh sangat nyata (P<0,01) terhadap kadar kolesterol, aktivitas antioksidan, warna, aroma dan rasa, sedangkan tidak berpengaruh nyata (P>0,05) terhadap kadar protein dan kadar lemak. Kesimpulan, pemberian ekstrak bunga rosela dengan metode evaporasi sebesar 5% dapat meningkatkan aktivitas antioksidan , aroma dan rasa daging se’i kambing, sedangkan untuk kadar kolesterol, kadar protein dan kadar lemak tidak berubah.

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Norman, G., S. Rice, E. Spackman, L. Stirk, A. Danso-Appiah, D. Suh, S. Palmer und A. Eastwood. „Trastuzumab for the treatment of HER2- positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction“. Health Technology Assessment 15, Suppl 1 (Mai 2011): 33–42. http://dx.doi.org/10.3310/hta15suppl1-04.

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This paper presents a summary of the evidence review group (ERG) report into trastuzumab for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic adenocarcinoma of the stomach (mGC) or gastro-oesophageal junction. HER2 positivity is defined by immunohistochemistry (IHC)3+ or IHC2+/fluorescence in situ hybridisation (FISH)+. The decision problem addressed was the testing of the whole mGC population with IHC and, for IHC2+ patients, also with FISH, followed by treatment of HER2-positive patients with trastuzumab combined with cisplatin and either capecitabine or 5-fluorouracil (5-FU) [HCX (trastuzumab, cisplatin, capecitabine)/fluorouracil (F)] compared with current standard NHS therapy. The manufacturer’s submission contained direct evidence from the ToGA trial, a well-conducted, multinational, phase III randomised controlled trial (RCT) that compared HCX/F with cisplatin and a fluoropyrimidine alone [cisplatin, capecitabine (CX)/F]. HCX/F showed statistically significantly better overall survival in the European Medicines Agency-licensed population subgroup (74%) (hazard ratio 0.65, 95% confidence interval 0.51 to 0.83), corresponding to median survival of 16 months versus 11.8 months. No other evidence exists for the efficacy of any therapy in a known HER2-positive mGC population; other comparisons extrapolate from trials in mixed HER2 status populations. The ERG accepted the manufacturer’s view that a meaningful network meta-analysis to establish a comparison for HCX/F compared with current standard NHS therapy [epirubicin, cisplatin, capecitabine (ECX)/epirubicin, oxaliplatin, capecitabine (EOX)/epirubicin, cisplatin, 5-FU (ECF)] was not possible, but was unconvinced by arguments advanced in the alternative narrative synthesis. These involved disregarding evidence from a meta-analysis and interpreting non-significant results of small RCTs comparing epirubicin-containing triplets with cisplatin, 5-FU (CF)/capecitabine (X) doublets as evidence of no difference between triplet and doublet regimens. The high CX/F dose in the ToGA trial was an additional basis for the contention of equivalence. An appropriate de novo economic evaluation, including an economic model that separately compared HCX or trastuzumab, cisplatin, 5-FU (HCF) with the triplet regimens ECX, EOX and ECF, based on a simple, three-state cohort model (progression-free, disease, progression and death), was submitted. Utility weights were applied to estimate quality-adjusted life-years (QALYs). Costs were assessed from an NHS perspective, and incorporated the acquisition and monitoring costs of the alternative regimens, HER2 testing, adverse events and other supportive care costs. An 8-year time horizon was used to represent a lifetime analysis. Results from the ToGA trial were combined with a series of assumptions on relative treatment effects and testing strategies. The manufacturer’s results produced an incremental cost-effectiveness ratio (ICER) of £53,010 per QALY for HCX versus ECX. Although the manufacturer undertook a detailed set of sensitivity analyses, several alternative model assumptions were not evaluated. The ERG undertook a series of alternative base-case analyses. As a result of these analyses, EOX replaced ECX as the appropriate comparator, and the ICER for the comparison of HCX vs EOX increased to between £66,982 and £71,636 per QALY. The impact of implementation of alternative testing strategies remained unclear. There is also considerable uncertainty surrounding the true estimate of effectiveness for the comparison between triplet regimens containing epirubicin (ECX/ECF/EOX) and doublet CX/F regimens. Consequently, the view of the ERG was that there is insufficient evidence on the efficacy of HCX/F compared with current NHS standard therapy for an ICER to be determined with any degree of certainty.

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Dapamawu, Rita, Gemini Malelak und Pieter Rihi Kale. „PENGARUH PEMBERIAN EKSTRAK TEPUNG ROSELA (Hibiscus sabdarifa Linn) TERHADAP SIFAT FISIK DAN KIMIA DENDENG BABI (The effect of roselle flour extract (hibiscus sabdariff linn) on the physical and chemical characteristics of pork jerky)“. JURNAL NUKLEUS PETERNAKAN 8, Nr. 1 (21.06.2021): 33–39. http://dx.doi.org/10.35508/nukleus.v8i1.3621.

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This study aimed was to determine the effect of roselle flour extract on pork jerky. Completely randomized design 4 x 3 was used in this experiment The treatment consisted of ER0 = without addition of roselle flour extract, ER4 = 4% (v/w) roselle flour extract, ER8 = roselle flour extract 8% (v/w) and ER12 = roselle flour extract 12%(v/w). The parameters observed were water content, fat oxidation, total bacteria, ph and organoleptic: color, aroma, and taste of park jerky. The result of statistical analysis showed that rosela flour exract on pork jerky had highly significantly effect (P<0.01) on water, fat oxidation, pH and organoleptics: colors, the aroma of pork jerky. The lowest water content was in ER12 (35.86±0.33), the lowest fat oxidation was in the ER12 (9.57±0.70), the lowest pH was in ER4 (4.79±0.05). The best color was found in ER4 (4.86±0.38), the best aroma was found in ER0 (5.00±0.00). In conclusion, increasing of roselle flour extract level causes the decreasing the oxidation fat, reducing the color score ( jerky become brown) and rosela/ sour in aroma.

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Ding, Xiaoya, J. Michael Alford und John C. Wright. „Lanthanide fluorescence from Er3+ in Er2@C82“. Chemical Physics Letters 269, Nr. 1-2 (April 1997): 72–78. http://dx.doi.org/10.1016/s0009-2614(97)00261-3.

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Çamlı, Kerem Yavuz, Recep Demirsöz, Mehmet Boy, Mehmet Erdi Korkmaz, Nafiz Yaşar, Khaled Giasin und Danil Yurievich Pimenov. „Performance of MQL and Nano-MQL Lubrication in Machining ER7 Steel for Train Wheel Applications“. Lubricants 10, Nr. 4 (23.03.2022): 48. http://dx.doi.org/10.3390/lubricants10040048.

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In the rail industry, there are four types of steel grades used for monoblock wheels, namely ER6, ER7, ER8 and ER9. ER7 steel is manufactured in accordance with the EN13262 standard and is utilized in European railway lines. These train wheels are formed by pressing and rolling after which they are machined using turning process to achieve their final dimensions. However, machining ER7 steels can be challenging due to their high mechanical properties, which can facilitate rapid tool wear and thermal cracking. Therefore, while the use of coolants is critical to improving their machinability, using conventional flood coolants adds extra operational costs, energy and waste. An alternative is to use minimum quantity lubrication (MQL) cooling technology, which applies small amounts of coolant mixed with air to the cutting zone, leaving a near-dry machined surface. In the current study, preliminary tests were undertaken under dry conditions and using coated carbide inserts to determine the optimal cutting parameters for machining ER7 steel. The impact of the cutting speed and feed rate on surface roughness (Ra), energy consumption and cutting temperature were investigated and used as a benchmark to determine the optimal cutting parameters. Next, additional machining tests were conducted using MQL and nano-MQL cooling technologies to determine their impact on the aforementioned machining outputs. According to preliminary tests, and within the tested range of the cutting parameters, using a cutting speed of 300 m/min and a feed rate of 0.15 mm/rev resulted in minimal surface roughness. As a result, using these optimal cutting parameters with MQL and Nano-MQL (NMQL) cooling technologies, the surface roughness was further reduced by 24% and 34%, respectively, in comparison to dry conditions. Additionally, tool wear was reduced by 34.1% and 37.6%, respectively. The overall results from this study demonstrated the feasibility of using MQL coolants as a sustainable machining alternative for steel parts for rail wheel applications. In addition, the current study highlight the enhanced performance of MQL cooling technology with the addition of nano additives.

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Ma, Lihua, Shiya Ma, Qisheng Tang, Mingmei Sun, Huizhe Yan, Xiuling Yuan, Wei Tian und Yufei Chen. „Environmental regulation effect on the different technology innovation-based the empirical analysis“. PLOS ONE 19, Nr. 1 (05.01.2024): e0296008. http://dx.doi.org/10.1371/journal.pone.0296008.

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This article explores the impact mechanism of different types of environmental regulations on corporate green technology innovation (GTI). The research focuses on analyzing three types of environmental regulations: command based environmental regulation (ER1), market-oriented environmental regulation (ER2), and voluntary environmental regulation (ER3), and how they affect corporate GTI. This study selected enterprise GTI as the dependent variable and measured it by the number of applications for green invention patents and green utility model patents. The independent variables are the three types of environmental regulations mentioned above. According to data from Chinese A-share listed companies. Using benchmark regression models to analyze the impact of different environmental regulations on GTI, and constructing a moderating effect model to study the role of corporate R&D investment and government support in the process of environmental regulations affecting GTI. The results indicate that (1) ER1, ER2, and ER3 can all promote enterprise GTI, and the three environmental regulatory methods have a better synergistic effect. (2) R&D investment has a positive correlation with the relationship between ER2 and GTI, and a negative correlation with ER 3 and ER 1. (3) There are differences in the GTI performance of enterprises in different regions, ownership nature, factor density, and industry types under the influence of environmental regulations. (4) The impact of environmental regulatory policies on corporate GTI is mainly short-term. This study provides a new perspective on how environmental regulations affect corporate GTI, especially in the context of developing countries like China. The research findings emphasize the role of different types of environmental regulations in incentivizing corporate GTI, while also pointing out factors that governments need to consider when formulating environmental policies, such as regional differences and corporate characteristics, which are of great significance for promoting green development of enterprises and achieving broader sustainable development goals.

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Park, Heum Gi, Velmurugu Puvanendran, Anne Kellett, Christopher C. Parrish und Joseph A. Brown. „Effect of enriched rotifers on growth, survival, and composition of larval Atlantic cod (Gadus morhua)“. ICES Journal of Marine Science 63, Nr. 2 (01.01.2006): 285–95. http://dx.doi.org/10.1016/j.icesjms.2005.10.011.

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Abstract Recently, the nutritional requirements of marine finfish larvae have received considerable attention, and studies have shown that docosahexaenoic acid (DHA) affects the growth and survival of marine finfish larvae. We investigated the effects of different rotifer diets containing variable amounts of DHA on the growth and survival of larval Atlantic cod (Gadus morhua L.). Four different commercial rotifer enrichment formulations were used: spray-dried whole cells composed of Crypthecodinium sp. (ED1), spray-dried whole cells of Schizochytrium sp. (ED2), an oil emulsion (ED3) and ED1, and dried Chlorella at a 7:3 ratio by weight (ED4). The resultant rotifers contained a similar concentration of DHA (1.1–1.6% DW), but the level of DHA differed in proportion to EPA for each enrichment, and was designated ER1–4. Twelve 30-l aquaria were used with three replicates per treatment. Larvae were fed with rotifers from 3 to 43 days post-hatch (dph) at 4000 prey l−1. At the end of the experiment, no significant differences were found in body length and dry weight between the larvae reared on ER1 and ER2. However, larvae reared on ER3 were significantly smaller (both in length and weight) than larvae reared on ER1 and ER2. Larval survival on the ER2 treatment at 43 dph was significantly higher than on the other three treatments. Our results showed a positive effect of rotifer DHA proportions on growth and survival of cod larvae, and demonstrated that Atlantic cod larvae require a high ratio of dietary DHA to EPA.

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Devi, Jyoti, Gyan P. Mishra, Vidya Sagar, Vineet Kaswan, Rakesh K. Dubey, Prabhakar M. Singh, Shyam K. Sharma und Tusar K. Behera. „Gene-Based Resistance to Erysiphe Species Causing Powdery Mildew Disease in Peas (Pisum sativum L.)“. Genes 13, Nr. 2 (08.02.2022): 316. http://dx.doi.org/10.3390/genes13020316.

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Globally powdery mildew (PM) is one of the major diseases of the pea caused by Erysiphe pisi. Besides, two other species viz. Erysiphe trifolii and Erysiphe baeumleri have also been identified to infect the pea plant. To date, three resistant genes, namely er1, er2 and Er3 located on linkage groups VI, III and IV respectively were identified. Studies have shown the er1 gene to be a Pisum sativum Mildew resistance Locus ‘O’ homologue and subsequent analysis has identified eleven alleles namely er1–1 to er1–11. Despite reports mentioning the breakdown of er1 gene-mediated PM resistance by E. pisi and E. trifolii, it is still the most widely deployed gene in PM resistance breeding programmes across the world. Several linked DNA markers have been reported in different mapping populations with varying linkage distances and effectiveness, which were used by breeders to develop PM-resistant pea cultivars through marker assisted selection. This review summarizes the genetics of PM resistance and its mechanism, allelic variations of the er gene, marker linkage and future strategies to exploit this information for targeted PM resistance breeding in Pisum.

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Fondevilla, S., J. I. Cubero und D. Rubiales. „Confirmation that the Er3 gene, conferring resistance to Erysiphe pisi in pea, is a different gene from er1 and er2 genes“. Plant Breeding 130, Nr. 2 (April 2011): 281–82. http://dx.doi.org/10.1111/j.1439-0523.2010.01769.x.

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