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1
Van Der Walt, J. H., and J. A. Carter. "The Effect of Different Pre-Operative Feeding Regimens on Plasma Glucose and Gastric Volume and pH in Infancy." Anaesthesia and Intensive Care 14, no. 4 (November 1986): 352–59. http://dx.doi.org/10.1177/0310057x8601400405.
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The effects of four different pre-operative feeding regimens were studied in 123 children below the age of one year presenting for surgery. Plasma glucose concentrations, blood acid-base values, gastric volume and gastric pH were measured before and after induction of anaesthesia. No patient was found to be hypoglycaemic and there were no significant differences in plasma glucose concentration and acid-base values between the groups. No correlation was demonstrated between the age and weight of the patients and the duration of fasting and the plasma glucose concentration. There was a significant elevation of plasma glucose concentration in all four groups after induction of anaesthesia (P<001) compared with the pre-induction level which is a reflection of the stress of blood sampling and induction of anaesthesia. Infants less than three months of age in the milk-feed group had a significantly higher gastric volume with low pH (P< 0.05) signifying a potentially greater risk of pulmonary acid aspiration. The practice of timing the last pre-operative feed in infancy according to the infant's normal feeding pattern does not appear to increase the risk factors for pulmonary aspiration, if milk is avoided.
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Dickmann, Iddo. "The Double-Mirror Gaze, Transcoded Testimony, and Disqualified Witnesses in the Talmud." Journal of Jewish Thought and Philosophy 31, no. 2 (September 6, 2023): 127–62. http://dx.doi.org/10.1163/1477285x-12341348.
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Abstract I will argue that the underlying rationale for the talmudic list of trades disqualified from legal testimony is aesthetic. These trades involved professional mimicry, which as such incapacitated what R. Neis has termed “homovisuality” or self-referential witnessing in the Talmud. Reading talmudic laws of conjoined testimony and the induction of witnesses in light of Deleuze’s and Blanchot’s philosophy, I will argue that homovisuality entailed the witness’s reincarnation as the subject of the event, thus re-signifying rather than reporting the event. The judge, transformed into a witness, could capture the truth of the event at a glance, in a manner both prior to and irreducible to trial procedures.
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Thind, Nancy, Pranav Sood, Rajeev Sood, and Geetika Gupta Syal. "Comparison of the efficacy, safety, acceptability and fetomaternal outcomes of combination of mifepristone and foley’s catheter with foley’s catheter alone in induction of labour in term pregnancies with previous lower segment caesarean section." International Journal of Reproduction, Contraception, Obstetrics and Gynecology 9, no. 10 (September 25, 2020): 4181. http://dx.doi.org/10.18203/2320-1770.ijrcog20204310.
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Background: Objective of the study was to compare the efficacy, safety, acceptability, fetomaternal outcomes of combination of mifepristone and Foley’s catheter with Foley’s catheter alone in induction of labor in term pregnancies with previous Lower segment caesarean section (LSCS).Methods: This was a prospective study of 36 women induced with mifepristone and foley’s catheter and 36 women induced with foley’s catheter alone at 37 weeks to 41+6 weeks with previous LSCS.Results: Mean bishop score on admission in combined group (2.44) was comparable with that of foley’s alone group (2.91, p=0.888). Mean Bishop score (BS) after foley’s expulsion in group A and group B was 7.46 and 6.33 respectively, which was statistically significant (p<0.001). In group A 69.5% of women delivered vaginally compared to 52.2% in group B which was comparable (p=0.230). Mean induction to delivery interval was significantly short in combination group (15.5±1.3 hours versus 20.8±1.07 hours, p=0.003). 50% women in group A required oxytocin for induction/ augmentation of labour as compared to 77.8% in group B (p=0.02). Failed induction was statistically higher in group B (p<0.05). No difference was found with regards scar dehiscence, scar rupture, Postpartum hemorrhage (PPH), wound infection, puerperal pyrexia, Meconium stained liquor (MSL), fetal distress, mean birth weight, 1 and 5 minutes Appearance, pulse, grimace, activity, and respiration (APGAR) score, neonatal outcome, hospital stay.Conclusions: Priming with mifepristone before insertion of foley’s catheter results in significant change in BS signifying that combination promotes early cervical ripening as compared to foley’s catheter alone. Mifepristone plays significant role in cervical ripening, reduces induction to delivery interval, oxytocin requirement and failed induction.
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Güneş, Eda. "Alteration in the oxidative status of Drosophila melanogaster Meigen (Diptera: Drosophilidae) fed with a diet containing Centaurea depressa M. Bieb. (Asteraceae)." Animal Biology 70, no. 2 (April 6, 2020): 227–37. http://dx.doi.org/10.1163/15707563-20191153.
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Abstract The aim of the this study was to evaluate the effects of fresh, dried and freeze-dried Centaurea depressa M. Bieb. (Asteraceae) on the oxidant and antioxidant status of the model organism D. melanogaster Meigen (Diptera: Drosophilidae) experimentally. The study was carried out from 2016 to 2019, and plant leaf extracts (0-50 mg/l) were added to insect standard artificial diets. The total protein, protein carbonyl content and glutathione-S-transferase, superoxide dismutase and catalase activities were quantified at the insect’s third larval stage. Our data showed that protein carbonyl content varied from 2.70 nmol/mg protein in the control group to 59.11 nmol/mg protein in the group fed with fresh leaf extract signifying induction of oxidative stress. All extracts increased the levels of all antioxidant enzymes and decreased the amounts of total protein. Meanwhile, the group fed with the freeze-dried extract showed no significant difference in the levels of total protein and protein carbonyl content except at the 50 mg/l concentration of the extract. Moreover, this group had superoxide dismutase and catalase activities 4 to 5 times higher than in the control group. In conclusion, induction of oxidative stress indicates that the fresh form of C. depressa leaves may have potential as a natural pesticide, whereas induction of endogenous antioxidant enzymes by the freeze-dried extract suggest its potential as an antioxidant.
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Park, Jiyeon, Gyeong Tae Eom, Joon Young Oh, Ji Hyun Park, Sun Chang Kim, Jae Kwang Song, and Jung Hoon Ahn. "High-Level Production of Bacteriotoxic Phospholipase A1 in Bacterial Host Pseudomonas fluorescens via ABC Transporter-Mediated Secretion and Inducible Expression." Microorganisms 8, no. 2 (February 11, 2020): 239. http://dx.doi.org/10.3390/microorganisms8020239.
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Bacterial phospholipase A1 (PLA1) is used in various industrial fields because it can catalyze the hydrolysis, esterification, and transesterification of phospholipids to their functional derivatives. It also has a role in the degumming process of crude plant oils. However, bacterial expression of the foreign PLA1-encoding gene was generally hampered because intracellularly expressed PLA1 is inherently toxic and damages the phospholipid membrane. In this study, we report that secretion-based production of recombinant PlaA, a bacterial PLA1 gene, or co-expression of PlaS, an accessory gene, minimizes this harmful effect. We were able to achieve high-level PlaA production via secretion-based protein production. Here, TliD/TliE/TliF, an ABC transporter complex of Pseudomonas fluorescens SIK-W1, was used to secrete recombinant proteins to the extracellular medium. In order to control the protein expression with induction, a new strain of P. fluorescens, which had the lac operon repressor gene lacI, was constructed and named ZYAI strain. The bacteriotoxic PlaA protein was successfully produced in a bacterial host, with help from ABC transporter-mediated secretion, induction-controlled protein expression, and fermentation. The final protein product is capable of degumming oil efficiently, signifying its application potential.
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Shalmani, Abdullah, Izhar Muhammad, Rahat Sharif, CaiPing Zhao, Uzair Ullah, Dong Zhang, Xiu-Qing Jing, et al. "Zinc Finger-Homeodomain Genes: Evolution, Functional Differentiation, and Expression Profiling Under Flowering-Related Treatments and Abiotic Stresses in Plants." Evolutionary Bioinformatics 15 (January 2019): 117693431986793. http://dx.doi.org/10.1177/1176934319867930.
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Zinc finger-homeodomain (ZHD) proteins constitute a plant-specific transcription factor family that play important roles in plant growth, development, and stress responses. In this study, we investigated a total of 10, 17, and 31 ZHD gene members in the peach, Arabidopsis, and apple genome, respectively. The phylogenetic tree divided the identified ZHD genes into 4 subfamilies based on their domain organization, gene structure, and motif distribution with minor variations. The ZHD gene family members were unevenly distributed throughout in apple, peach, and Arabidopsis genomes. Segmental duplication was observed for 14 pairs of genes in apple. Transcript analysis found that ZHD genes mostly expressed in various tissues, particularly in leaves and flowers. Moreover, the transcript of most ZHD genes was significantly affected at different time points in response to various flowering-related exogenous hormones (sugar, gibberellin [GA], and 6-benzylaminopurine [6-BA]), signifying their possible role in the flowering induction in apple. Furthermore, the transcripts of CaZHD6, CaZHD7, CaZHD3, and CaZHD8 have induced in response to abiotic stresses including heat, drought, salt, and cold, indicating their possible involvement in response to abiotic stresses. Our research work systemically presents the different roles of ZHD genes. We believe that this study will provide a platform for future functional characterization of ZHD genes and to deeply unfold their roles in the regulation of flowering induction in plants.
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Sporn, S. A., D. F. Eierman, C. E. Johnson, J. Morris, G. Martin, M. Ladner, and S. Haskill. "Monocyte adherence results in selective induction of novel genes sharing homology with mediators of inflammation and tissue repair." Journal of Immunology 144, no. 11 (June 1, 1990): 4434–41. http://dx.doi.org/10.4049/jimmunol.144.11.4434.
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Abstract Adherence of monocytes to endothelial cells or extracellular matrices is likely to play a critical role in triggering monocyte activation in extravascular sites of infection, chronic inflammatory disorders, tissue damage and neoplastic growth. We have constructed a cDNA library from monocytes adhered for 30 min on plastic and have screened it by differential hybridization for mRNA rapidly induced by adherence. Two of the cDNA isolated have been identified as IL-1 beta and superoxide dismutase. Sequence data from three other adherence specific clones demonstrates the presence of ATTTA mRNA instability sequences in their 3' untranslated regions signifying inflammation-associated genes. The deduced amino acid sequences indicate the presence of open reading frames with sequence homologies to a family of host defense cytokines, one of them being identified as IL-8. Of the 14 clones initially identified, 4 have been analyzed for induction of mRNA expression. Although 3 of the 4 clones were equally induced by PMA and LPS under nonadherent conditions, all 4 cDNA showed distinct patterns of induction with adherence to extracellular matrix components or endothelial cells. The deduced amino acid sequence homologies indicate that we have isolated cDNA that code for three unique gene products. These cDNA belong to a gene family of early host defense cytokines involved in inflammation and cell growth, but which are differentially regulated by adherence to different surfaces.
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Hart, Abarasi, Mohamed Adam, John P. Robinson, Sean P. Rigby, and Joseph Wood. "Tetralin and Decalin H-Donor Effect on Catalytic Upgrading of Heavy Oil Inductively Heated with Steel Balls." Catalysts 10, no. 4 (April 3, 2020): 393. http://dx.doi.org/10.3390/catal10040393.
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The Toe-to-Heel Air Injection (THAI) combined with catalytic upgrading process in situ (CAPRI) has demonstrated it can simultaneously extract and upgrade heavy oil in situ. This paper reports the investigation of augmenting temperature deficit and suppressing coke formation in the CAPRI section through the incorporation of induction heating and H-donor solvents. An induction-heated catalytic reactor was designed and developed, heated with steel balls in a mixed bed of NiMo/Al2O3 catalyst (66% v/v) to 425 °C temperature, 15 bar pressure and 0.75 h−1 LHSV (Liquid Hourly Space Velocity). The catalyst surface area, pore volume and pore size distribution were determined by using nitrogen adsorption–desorption, while the location of coke deposits within the microstructure of the pelleted spent catalyst was analyzed with X-ray nano-Computed Tomography (X-ray nano-CT). Findings showed that induction heating improved the catalyst performance, resulting in a 2.2° American Petroleum Institute (API) gravity increase of the upgraded oil over that achieved with the conventional heating method. The increment in API gravity and viscosity reduction in the upgraded oils with nitrogen gas only, N2 and H-donor solvents, and hydrogen gas environments can be summarized as follows: decalin > H2 gas >= tetralin > N2 gas. Meanwhile, the improvement in naphtha fraction, middle distillate fractions and suppression of coke formation are as follows: decalin > H2 gas > tetralin > N2 gas. The X-ray nano-CT of the spent catalyst revealed that the pellet suffers deactivation due to coke deposit at the external surface and pore-mouth blockage, signifying underutilization of the catalyst interior surface area.
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Robb, Lindsey, and Sheena Moffat. "Transition to Postgraduate Study at Master’s Level Lessons Learned:." Journal of Perspectives in Applied Academic Practice 8, no. 1 (September 1, 2020): 41–51. http://dx.doi.org/10.14297/jpaap.v8i1.402.
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Evidence from UK universities’ Postgraduate Taught Experience Survey (PTES) concluded that whilst confident and experienced in their area of practice, some find the prospect of returning to study in an on-line environment and making the transition to Master’s Level daunting. In recognition of this, a small group created an online resource ‘Preparation for study at Master’s Level’ which students have access to as part of the induction process for the taught postgraduate programme, MSc in Advanced Practice in the School of Health and Social Care at Edinburgh Napier University.
This paper reports on findings of an evaluation of the on-line induction resource using NOVI survey to explore student’s views. 73% of respondents (n=25) felt that the online resource was helpful in increasing confidence about online learning and studying at Master’s level. Qualitative comments reflect other research signifying the importance of social interaction and ongoing support to co-create understanding and development of skills. The lessons learned from students’ lived experience informed amendments to programme online and face to face content and had an impact on the programme team by rekindling a programme focus.
Though particular to one programme within one university, the findings mirror themes highlighted elsewhere; that transition to Master’s level is complex, involving change and exploration of identity, anxiety about what Master’s level entails, all of which make for an emotionally challenging experience. Others who support postgraduate students studying at Master’s level, can learn from this experience.
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Bell, Erica, Amy Webb, Joseph Stanek, Megan Blue, Parth Patel, Diana Thomas, Christopher Pierson, et al. "BIOM-49. A PILOT STUDY OF CEREBROSPINAL FLUID EXOSOMAL SMALL RNA-SEQUENCING IN PEDIATRIC MEDULLOBLASTOMA PATIENTS ON THE NEXT CONSORTIUM “HEAD START” 4 PROTOCOL." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii15—vii16. http://dx.doi.org/10.1093/neuonc/noac209.059.
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Abstract BACKGROUND Head Start 4 is a randomized clinical trial to determine whether dose-intensive tandem consolidation, compared with a single cycle, with autologous hematopoietic progenitor cell rescue provides a survival benefit in pediatric patients with medulloblastoma or other embryonal tumors. The trial incorporates upfront molecular subgrouping and non-mandatory, prospective blood and cerebrospinal fluid (CSF) collection. This pilot study aimed to identify exosomal non-coding RNAs (exo-ncRNAs) that might serve as novel diagnostic and/or treatment response biomarkers. METHODS CSF(1-2mLs) from 11 controls (non-tumor) and 27 medulloblastoma participants including 23 obtained at baseline, 22 at the end of induction, 3 post-consolidation, and 4 relapse time points, were profiled. Exosome isolation and small RNA-sequencing were performed by System Biosciences. Differential gene expression (DGE) was performed in R (DESeq2). Variations in gene expression profiles between samples were visualized using principal component analysis. RESULTS After limiting to ncRNAs with expression of 2 counts per million in 50% or more of the samples in each comparison, ~9,500 ncRNAs were detected. DGE analyses revealed 118 ncRNAs with log2 fold change(FC) >2 and 1 ncRNA with log2FC< -2 in baseline CSF samples compared to controls. In contrast, 11 ncRNAs(log2FC >2) and 1 ncRNA(log2FC< -2) were detected in end of induction CSF samples compared to controls. Comparing end of induction to baseline CSF samples accounting for paired samples, 0 ncRNAs(log2FC >2) and 52 ncRNAs(log2FC< -2) were detected. CONCLUSIONS Overall, our data indicate that exosomal small RNA-sequencing of limited CSF volumes is feasible. Differential expression and distinct clustering between tumor baseline samples compared to non-tumor controls was observed. CSF-derived exo-ncRNAs at end of induction also demonstrated “normalization” of ncRNA profiles, signifying CSF biomarkers may serve a role in diagnosis and molecular response assessment. A comprehensive analysis including multi-marker predictive model development and molecular subgrouping will be undertaken at completion of study enrollment.
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Al-Bayati, Ammar I., Ammar A. Razzak Mahmood, Zainab A. Al-Mazaydeh, Majdoleen S. Rammaha, Rheda I. Al-bayati, Fatima Alsoubani, and Lubna H. Tahtamouni. "Synthesis, docking study, and in vitro anticancer evaluation of new flufenamic acid derivatives." Pharmacia 68, no. 2 (May 21, 2021): 449–61. http://dx.doi.org/10.3897/pharmacia.68.e66788.
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Novel compounds (6–10) were synthesized and confirmed by spectroscopic analysis, including AT-IR, 1HNMR and CHNS. Their cytotoxic effect was evaluated by MTT assay against two cancer cell lines and two normal cell types. Compound 7 exhibited anticancer activity against MCF-7 breast cancer cell line (GI50 = 63.9 µg/ml, 148 µM), without any effect against A549 lung cancer cells, or the normal cells. Compound 7 caused cytotoxicity in MCF-7 breast cancer cells by apoptotic cell death, as suggested by fragmented nuclei after DAPI staining and agarose gel electrophoresis. In addition, treating MCF-7 cells with compound 7 resulted in an increase in the level of caspase 9 mRNA level, and its activation. Moreover, compound 7-treated MCF-7 cells showed enhanced cytochrome c release from the mitochondria to the cytosol, signifying an induction of the intrinsic apoptotic pathway. Finally, compound 7 exhibited epidermal growth factor receptor (EGFR) kinase inhibitory activity at (EC50 = 0.13 µM), which was matched by molecular docking studies that showed compound 7 might be an important EGFR kinase inhibitor.
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Kelly, Ronan Joseph, Kellie Nicole Smith, Valsamo Anagnostou, Elizabeth Thompson, Russell K. Hales, Richard J. James Battafarano, K. Ranh Voong, et al. "Neoadjuvant nivolumab plus concurrent chemoradiation in stage II/III esophageal/gastroesophageal junction cancer." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 142. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.142.
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142 Background: Neoadjuvant chemoradiation (cRT) prior to surgical resection in stage II/III esophageal/gastroesophageal junction (E/GEJ) cancer results in a complete pathologic response rate (pCR) of 20-30%. The appearance of favorable microenvironment features (enhanced tumor infiltrating lymphocytes, perivascular lymphocytes and tertiary lymphoid structures) after induction therapy in resected EC suggest early stage tumors may respond favorably to immune based therapy and in particular to PD-1 blockade when combined with cRT. Methods: In this pilot study, we administered 2 cycles of induction nivolumab (N) q2 weekly prior to standard of care carboplatin/paclitaxel/radiation plus 3 additional cycles of N on week 1, 3 and 5 of cRT. An Ivor-Lewis esophagectomy (E/MIE) was performed 6-10 weeks after the last IO dose. The primary endpoints of the study were safety and feasibility. We also evaluated the pCR, survival and temporal dynamics of T cell receptor clonotypes. Results: Between August 2017 and July 2018, 16 patients were enrolled on study. Induction N and neoadjuvant N combined with cRT in stage II/III E/GEJ cancers has an acceptable toxicity profile and was not associated with delays in surgery. Toxicities of note include steroid responsive grade 3 dermatitis (1/16), grade 3 hepatitis (1/16) and no cases of pneumonitis. To date, 10 patients with E adenocarcinoma have had an E/MIE and the pCR is 4/10 (40%). T cell receptor sequencing of the tumor bed and serial peripheral blood T cells revealed high peripheral representation of tumor-associated T cells. In one notable case, the highest-frequency intratumoral clone decreased in frequency in the peripheral blood upon treatment and rapidly increased after surgical resection, potentially signifying trafficking to the tumor site. Conclusions: Induction N and N combined with cRT has limited side-effects, did not result in surgical delay or enhanced surgical morbidity/mortality and induced a pCR of 40% in stage II/III E/GEJ cancers. Additional efficacy data on the full cohort and more in depth correlative studies will be presented to validate systemic activation of anti-tumor T cell responses. Clinical trial information: NCT03044613.
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Medzikovic, Lejla, Hylja Heese, Pieter B. van Loenen, Cindy P. A. A. van Roomen, Ingeborg B. Hooijkaas, Vincent M. Christoffels, Esther E. Creemers, Carlie J. M. de Vries, and Vivian de Waard. "Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes." International Journal of Molecular Sciences 22, no. 4 (February 5, 2021): 1600. http://dx.doi.org/10.3390/ijms22041600.
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Fibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myofibroblasts (MyoFB), which are the key mediators of the fibrotic response. Additionally, cardiomyocytes are involved by providing pro-fibrotic cues. Nuclear receptor Nur77 is known to reduce cardiac hypertrophy and associated fibrosis; however, the exact function of Nur77 in the fibrotic response is yet unknown. Here, we show that Nur77-deficient mice exhibit severe myocardial wall thinning, rupture and reduced collagen fiber density after myocardial infarction and chronic isoproterenol (ISO) infusion. Upon Nur77 knockdown in cultured rat CFs, expression of MyoFB markers and extracellular matrix proteins is reduced after stimulation with ISO or transforming growth factor–β (TGF-β). Accordingly, Nur77-depleted CFs produce less collagen and exhibit diminished proliferation and wound closure capacity. Interestingly, Nur77 knockdown in neonatal rat cardiomyocytes results in increased paracrine induction of MyoFB differentiation, which was blocked by TGF-β receptor antagonism. Taken together, Nur77-mediated regulation involves CF-intrinsic promotion of CF-to-MyoFB transition and inhibition of cardiomyocyte-driven paracrine TGF-β-mediated MyoFB differentiation. As such, Nur77 provides distinct, cell-specific regulation of cardiac fibrosis.
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Abou Najem, Sonia, Ghada Khawaja, Mohammad Hassan Hodroj, Patil Babikian, and Sandra Rizk. "Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells." Cells 8, no. 12 (November 21, 2019): 1480. http://dx.doi.org/10.3390/cells8121480.
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Atypical epigenetic processes including histone acetylation and DNA methylation have been identified as a fundamental theme in hematologic malignancies. Such mechanisms modify gene expression and prompt, in part at least, the initiation and progression of several malignancies including acute myeloid leukemia. In the current study we determined the effects of treating KG-1 and U937 acute myeloid leukemia (AML) cells, in vitro, with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), or with a DNMT inhibitor, decitabine (DAC), or their combination, on cell proliferation, cell cycle progression, apoptosis, and expression of apoptosis-related proteins. Each of SAHA and DAC attenuated cell proliferation and induced cell cycle arrest and apoptotic cell death of KG-1 and U937 cell lines. Besides, their sequential combination improved the obtained anti-neoplastic effect: significant augmentation of growth inhibition and apoptosis induction as compared to cells treated with either drug alone. This effect was featured by the upregulated expression of Bax, cytochrome c1, p21, and cleaved caspases 8, 9, and 3, signifying the activation of both the intrinsic and extrinsic pathways of apoptosis. The sequential combination of SAHA and DAC causes a profound antitumorigenic effect in AML cell lines by inducing the expression of tumor suppressor genes.
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van Niekerk, Gustav, Ashwin W. Isaacs, Theo Nell, and Anna-Mart Engelbrecht. "Sickness-Associated Anorexia: Mother Nature’s Idea of Immunonutrition?" Mediators of Inflammation 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/8071539.
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During an infection, expansion of immune cells, assembly of antibodies, and the induction of a febrile response collectively place continual metabolic strain on the host. These considerations also provide a rationale for nutritional support in critically ill patients. Yet, results from clinical and preclinical studies indicate that aggressive nutritional support does not always benefit patients and may occasionally be detrimental. Moreover, both vertebrates and invertebrates exhibit a decrease in appetite during an infection, indicating that such sickness-associated anorexia (SAA) is evolutionarily conserved. It also suggests that SAA performs a vital function during an infection. We review evidence signifying that SAA may present a mechanism by which autophagic flux is upregulated systemically. A decrease in serum amino acids during an infection promotes autophagy not only in immune cells, but also in nonimmune cells. Similarly, bile acids reabsorbed postprandially inhibit hepatic autophagy by binding to farnesoid X receptors, indicating that SAA may be an attempt to conserve autophagy. In addition, augmented autophagic responses may play a critical role in clearing pathogens (xenophagy), in the presentation of epitopes in nonprovisional antigen presenting cells and the removal of damaged proteins and organelles. Collectively, these observations suggest that some patients might benefit from permissive underfeeding.
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Lesur, Isabelle, and Judith L. Campbell. "The Transcriptome of Prematurely Aging Yeast Cells Is Similar to That of Telomerase-deficient Cells." Molecular Biology of the Cell 15, no. 3 (March 2004): 1297–312. http://dx.doi.org/10.1091/mbc.e03-10-0742.
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To help define the pathologies associated with yeast cells as they age, we analyzed the transcriptome of young and old cells isolated by elutriation, which allows isolation of biochemical quantities of old cells much further advanced in their life span than old cells prepared by the biotin-streptavidin method. Both 18-generation-old wild-type yeast and 8-generation-old cells from a prematurely aging mutant (dna2-1), with a defect in DNA replication, were evaluated. Genes involved in gluconeogenesis, the glyoxylate cycle, lipid metabolism, and glycogen production are induced in old cells, signifying a shift toward energy storage. We observed a much more extensive generalized stress response known as the environmental stress response (ESR), than observed previously in biotin-streptavidin-isolated cells, perhaps because the elutriated cells were further advanced in their life span. In addition, there was induction of DNA repair genes that fall in the so-called DNA damage “signature” set. In the dna2-1 mutant, energy production genes were also induced. The response in the dna2-1 strain is similar to the telomerase delete response, genes whose expression changes during cellular senescence in telomerase-deficient cells. We propose that these results suggest, albeit indirectly, that old cells are responding to genome instability.
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Arjunan, Pachiappan, Radhika Swaminathan, Jessie Yuan, Mohamed Elashiry, Amany Tawfik, Mohamed Al-Shabrawey, Pamela M. Martin, Thangaraju Muthusamy, and Christopher W. Cutler. "Exacerbation of AMD Phenotype in Lasered CNV Murine Model by Dysbiotic Oral Pathogens." Antioxidants 10, no. 2 (February 18, 2021): 309. http://dx.doi.org/10.3390/antiox10020309.
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Emerging evidence underscores an association between age-related macular degeneration (AMD) and periodontal disease (PD), yet the biological basis of this linkage and the specific role of oral dysbiosis caused by PD in AMD pathophysiology remains unclear. Furthermore, a simple reproducible model that emulates characteristics of both AMD and PD has been lacking. Hence, we established a novel AMD+PD murine model to decipher the potential role of oral infection (ligature-enhanced) with the keystone periodontal pathogen Porphyromonas gingivalis, in the progression of neovasculogenesis in a laser-induced choroidal-neovascularization (Li-CNV) mouse retina. By a combination of fundus photography, optical coherence tomography, and fluorescein angiography, we documented inflammatory drusen-like lesions, reduced retinal thickness, and increased vascular leakage in AMD+PD mice retinae. H&E further confirmed a significant reduction of retinal thickness and subretinal drusen-like deposits. Immunofluorescence microscopy revealed significant induction of choroidal/retinal vasculogenesis in AMD+PD mice. qPCR identified increased expression of oxidative-stress, angiogenesis, pro-inflammatory mediators, whereas antioxidants and anti-inflammatory genes in AMD+PD mice retinae were notably decreased. Through qPCR, we detected Pg and its fimbrial 16s-RrNA gene expression in the AMD+PD mice retinae. To sum-up, this is the first in vivo study signifying a role of periodontal infection in augmentation of AMD phenotype, with the aid of a pioneering AMD+PD murine model established in our laboratory.
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Sarathbabu, Subbarayan, Satheesh K. Marimuthu, Souvik Ghatak, Subramanian Vidyalakshmi, Guruswami Gurusubramanian, Sankar K. Ghosh, Selvi Subramanian, Wenqing Zhang, and Nachimuthu S. Kumar. "Induction of Apoptosis by Pierisin-6 in HPV Positive HeLa and HepG2 Cancer Cells is Mediated by the Caspase-3 Dependent Mitochondrial Pathway." Anti-Cancer Agents in Medicinal Chemistry 19, no. 3 (June 25, 2019): 337–46. http://dx.doi.org/10.2174/1871520619666181127113848.
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Background: To explore the cytotoxic and apoptotic activity of the pierisin-6 protein in HPV HeLa and HepG2 cell lines. Methods: In this study, isolation, and purification of cytotoxic Prierisin-6 from the larvae of Pieris napi by affinity column chromatography techniques. Characterization of full-length mRNA of pierisin-6 gene was performed using 3’/5’ RACE PCR. The quantitative RT-PCR used to study the developmental stage-specific expression of pierisin-6 mRNA. The most effective concentration of Pierisin-6 protein was determined by measuring cell proliferation. Apoptosis was assessed using AO/Et-Br, Propidium Iodide, and Rhodamine 123 assays, whereas protein levels of caspase 3, cytochrome C were evaluated by ELISA method. Pierisin-6 induced cell cycle arrest was determined using Propidium iodide by FACS. Results: In this study, Pierisin-6, a novel apoptotic protein was found to have cytotoxicity against HeLa, HepG2 human cancer cell lines and L-132 human lung epithelial cell line. Among the target cells, HeLa was the most sensitive to Pierisin-6. Flow cytometry analysis confirms an increased percentage of apoptotic cells in sub G1 phase and cell cycle arrest at S phase. Alteration in the transmembrane potential of mitochondria, Cytochrome c released from the mitochondrial membrane, and caspase substrate assay demonstrated the cleavage of Ac- DEVD-pNA signifying the activation of Caspase-3. These findings suggested that Pierisin-6 significantly induce apoptosis in HeLa and HepG2 cells and is attributed mainly through a mitochondrial pathway by activation of caspases. The developmental and stage-specific expression of pierisin-6 mRNA was one thousand-fold increased from second to third instar larvae and gradually declined before pupation. Conclusion: Pierisin-6 represents a promising therapeutic approach for liver cancer patients.
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Perez, Giselle K., Fangxin Hong, Andrew M. Evens, Thomas M. Habermann, Ranjana Advani, Stephen M. Ansell, Puneet S. Cheema, et al. "Patient-Reported Outcomes Among Patients with High-Risk Untreated Follicular Lymphoma (FL) Randomized to Bendamustine/Rituximab (BR) or Bendamustine/Rituximab with Bortezomib (BVR) Therapy: Results from the ECOG-ACRIN E2408 Study." Blood 136, Supplement 1 (November 5, 2020): 45–46. http://dx.doi.org/10.1182/blood-2020-140502.
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Introduction: FL is the most common indolent non-Hodgkin lymphoma in the Western world. FL may cause disease-related symptoms, and patients with high-risk disease usually require systemic therapy. BR is commonly used as first-line therapy for high-risk FL, and the addition of bortezomib to a BR backbone has been studied (Evens A et al. Clin Can Res 2020). Little is known about how these therapeutic options impact patients' health-related quality of life (HRQL). To fill this gap, patient-reported outcomes (PROs) were administered to patients enrolled on E2408 to quantify symptom burden and effects of BR versus BVR induction on HRQL. Methods: Patients (n=258) randomized to receive 6 cycles of BR or BVR induction completed PROs assessing neurotoxicity (FACT/GOG-Ntx) at the beginning of each treatment cycle. Additional PROs measuring fatigue (FACT-F), lymphoma-specific concerns (FACT-Lym) and HRQL (Functional Assessment of Cancer Therapy-General; FACT-G) were completed at baseline, mid-treatment (MT; cycle 3/4) and end of induction (EOI; cycle 6). Paired t-test was used to assess PRO score changes from baseline to MT and EOI within BR or BVR group. Two-sample t-test was used to compare change scores between groups at MT and EOI, respectively. Univariate analyses with a linear model identified patient baseline characteristics and clinical factors (age, sex, stage, performance status, # extra nodal sites, FLIPI, GELF, bone marrow involvement, elevated LDH, palpable splenomegaly, B-symptoms, CRIS) associated with PRO change scores from baseline to EOI, adjusting for treatment group. A multivariate model was built with backward variable selection approach for each of the PROs. Results: As shown in Figure 1, compared with baseline, patients randomized to BVR reported significantly worse FACT/GOG-Ntx scores at cycle 4, which continued to end of induction (FACT/GOG-Ntx change scores -2.91 to -3.73; p < 0.001). Neurotoxicity remained stable for patients treated with BR (Ntx change scores -0.02 to -0.55). FACT-Fatigue scores indicated worse fatigue at MT compared to baseline for patients receiving BVR (-2.7, p<0.05), yet they remained stable for BR. FACT-Lym scores were significantly higher at MT (BR: 2.69, p<0.001; BVR: 2.71, p=0.007) and end of induction (BR: 3.32, p<0.001; BVR: 3.55, p<0.001) compared to baseline, signifying a reduction in lymphoma-related symptoms in both arms. FACT-G scores were comparable between treatment arms at each time-point and did not change significantly from baseline to end of induction. Univariate analyses among all patients identified older age and the absence of palpable splenomegaly at baseline as associated with worse FACT-Lym, FACT-Fatigue, and FACT-G change scores, signifying less improvement in lymphoma-related symptoms, fatigue and HRQL from baseline to end of induction (p<0.01). The presence of B-symptoms at baseline was associated with a greater reduction in lymphoma-related symptoms and fatigue from baseline to end of induction (p<0.01). Higher ECOG performance status was only associated with higher FACT-Fatigue change score, suggesting more improvement in fatigue for those with worse performance status at baseline. A multivariate model generated similar results. Conclusions: Despite worse treatment-related symptoms throughout induction, the addition of bortezomib was associated with comparable overall HRQL to those treated with BR. Both treatments were associated with a reduction in lymphoma-related symptoms from baseline to end of induction, likely contributing to stable HRQL throughout treatment despite treatment-related symptoms. Findings also suggest that a subgroup of patients, particularly those who are older, may experience fewer improvements in lymphoma-related symptoms. This underscores the potential need for closer monitoring and clinical management of these patients. Collectively, results are likely to be encouraging for patients experiencing lymphoma-related symptoms, for whom the symptom burden associated with treatment may be worth the trade-off given the potential for improved disease-related symptom control. Disclosures Evens: Merck: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Research Funding; Mylteni: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Advani:Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding; Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy. Ansell:Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding. Winter:Norvartis: Consultancy, Other: DSMB; Ariad/Takeda: Consultancy; CVS/Caremark: Consultancy; Delta Fly Pharma: Consultancy; Amgen: Consultancy; Epizyme: Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Cella:FACIT.org: Membership on an entity's Board of Directors or advisory committees, Other: President; Astellas: Consultancy, Honoraria; Pled Pharma: Research Funding; Janssen: Research Funding; Clovis: Research Funding; Alexion: Research Funding; Apellis: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Kiniksa: Consultancy; IDDI: Consultancy; BMS: Consultancy, Research Funding; ASAHI KASEI PHARMA CORP.: Consultancy; Oncoquest: Consultancy; Mei Pharma: Consultancy; Ipsen: Consultancy, Research Funding; Evidera: Consultancy; DSI: Consultancy, Research Funding; BlueNote: Consultancy; Abbvie: Consultancy, Research Funding; PROMIS Health Org: Membership on an entity's Board of Directors or advisory committees, Other. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acerta: Consultancy, Research Funding. Wagner:Celgene Inc.: Membership on an entity's Board of Directors or advisory committees; Connect Multiple Myeloma Registry: Membership on an entity's Board of Directors or advisory committees.
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Tasho, Reep Pandi, Song-Hee Ryu, and Jae-Young Cho. "Effect of Sulfadimethoxine, Oxytetracycline, and Streptomycin Antibiotics in Three Types of Crop Plants—Root, Leafy, and Fruit." Applied Sciences 10, no. 3 (February 7, 2020): 1111. http://dx.doi.org/10.3390/app10031111.
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(1) Background: Plants act as the natural sink for a variety of toxins in the environment, including veterinary antibiotics (VAs). The objective of this study was to evaluate the uptake and fate of sulfadimethoxine (SDZ), oxytetracycline (OTC), and streptomycin (STR) in lettuce (Lactuca sativa L.), carrot (Daucus carota), and pepper (Capsicum annum) grown in VAs amended soil. (2) Methods: 0, 50, and 100 mg kg−1 VA laced manure was applied in a sandy clay loam soil. (3) Results: 30-d (lettuce) and 60-d (carrot and pepper) greenhouse experiment showed that SDZ and OTC were taken up by all three plants, with concentrations in plant tissue ranging from 0.1 to 1.2 mg kg−1 dry weight. The concentration of VAs in plant tissues increased with a corresponding increase of antibiotics in manure. The highest plant tissue concentrations were found in carrot and lettuce, followed by pepper. An increase in NADPH P450 reductase and glutathione-s-transferase enzyme activity with increasing SDZ and OTC concentration was evident, signifying the induction of the detoxification process. The activity of plant detoxification enzymes under STR treatment was found not to be significantly different from control. (4) Conclusions: These results raise potential human health concerns of consuming low levels of antibiotics from produce grown on manure-amended soils. The result indicates that SDZ, OTC, and STR antibiotics posed high, medium, and low acute ecological risks in lettuce, carrot, and pepper plants when grown in sandy clay loam soil.
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Khafagy, El-Sayed, Ahmed Al Saqr, Hadil Faris Alotaibi, and Amr Selim Abu Lila. "Cytotoxic and Apoptotic Effect of Rubus chingii Leaf Extract against Non-Small Cell Lung Carcinoma A549 Cells." Processes 10, no. 8 (August 5, 2022): 1537. http://dx.doi.org/10.3390/pr10081537.
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Rubus chingii is a traditional Chinese medicinal herbal that has been used since ancient times for its great dietary and medicinal values. Recent reports have underscored the promising cytotoxic effect of R. chingii extracts against a wide variety of cancer cells. Therefore, in the current study, we aim to explore the anticancer potential of the Rubus chingii ethanolic leaf extract (RcL-EtOH) against non-small cell lung cancer A549 cells. RcL-EtOH efficiently exerted a cytotoxic effect against A549 cells in a dose dependent manner, whilst, it exhibited non-significant toxic effects on normal murine macrophage cells, signifying its safety against normal cells. The reduced viability of A549 cells was reaffirmed by the acridine orange/ethidium bromide double staining, which confirmed the induction of apoptosis in RcL-EtOH-treated A549 cells. In addition, RcL-EtOH instigated the dissipation of mitochondrial membrane potential (ΔΨm) with mutual escalation in ROS generation in a dose-dependent manner. Furthermore, RcL-EtOH increased caspase-3, caspase-9 levels in A549 cells post-exposure to RcL-EtOH, which was concomitantly followed by altered mRNA expression of apoptotic (anti-apoptotic: Bcl-2, BclXL; pro-apoptotic: Bax, Bad). To sum up, the RcL-EtOH-instigated apoptotic cell death within A549 cells was assumed to be accomplished via targeting mitochondria, triggering increased ROS generation, with subsequent activation of caspase cascade and altering the expression of gene regulating apoptosis. Collectively, RcL-EtOH might represent a plausible therapeutic option for the management of lung cancer.
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Reade, Julia. "Black Noise from the Break: Ma and Pa’s Black Radical Lyricism." Humanities 12, no. 2 (April 19, 2023): 35. http://dx.doi.org/10.3390/h12020035.
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Kendrick Lamar’s 2022 track “We Cry Together” is, if nothing else, a masterful piece of wordplay and rhythm. Lamar manages to create a lyrical conversation that sounds both dialectical and diametric. Both the song and album are a definitive break from his earlier tenor that struck a mass appeal. A private conversation between two people, “We Cry Together”, insofar as it captures the intimate interiority of a couple, is also a break within the album itself. Textual renderings of Black performances cut away in ways similar to Lamar’s song or the soloist in a jazz ensemble, their breaks signifying sound. Invoking as aural praxis the language of jazz musicology and Black lyrical theory of Fred Moten, this article closely reads chapter four in George Lamming’s In the Castle of My Skin as one such special representation of textual aurality. First, it identifies multiple manifestations of “the break” before probing the deeply conflicted concept of Black noise as the racialized, resistant, resilient, and resonant octave of radical Black performance. A lyrical improvisation of a Black noise defiant in its indeterminacy, Ma and Pa’s duet cuts away from Castle’s polyphonic ensemble, creating the break within a break, within a break. Lingering in the cut, listening as Fred Moten, Douglas Kearney, Ren Ellis Neyra, and Zadie Smith encourage, the article arrives at a euphonic reproduction as induction into a legacy of synesthetic, lyrical, radical Black noise.
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Gao, Ke, Chengfei Zhang, Yihong Tian, Sajid Naeem, Yingmei Zhang, and Yongmei Qi. "The role of endoplasmic reticulum stress in lead (Pb)-induced mitophagy of HEK293 cells." Toxicology and Industrial Health 36, no. 12 (November 10, 2020): 1002–9. http://dx.doi.org/10.1177/0748233720971882.
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It is well-documented that lead (Pb) toxicity can affect almost all systems in living organisms. It can induce selective autophagy of mitochondria (mitophagy) by triggering reactive oxygen species production. Emerging evidence has suggested that Pb-induced autophagy can also be activated by the endoplasmic reticulum (ER) stress pathway. However, the interplay between ER stress and mitophagy remains to be elucidated. In this study, human embryonic kidney HEK293 cells were employed to investigate the role of ER stress in Pb-induced mitophagy. The results showed that the cell viability was decreased and cell damage was induced after exposure to Pb (0, 0.5, 1, 2, and 4 mM) for 24 h in a dose-dependent manner. Moreover, the expression of LC3-Ⅱ was significantly increased, and the expression of HSP60 was dramatically decreased after exposure to 1 mM and 2 mM Pb, indicating the induction of mitophagy following Pb exposure. Meanwhile, the expressions of activating transcription factor 6, inositol-requiring protein-1α, CCAAT/enhancer binding protein homologous protein, and glucose-regulated protein 78 were dramatically increased after Pb treatment, signifying the initiation of ER stress. Notably, the mitophagic effect was significantly compromised when ER stress was inhibited by 0.5 mM 4-phenylbutyrate, which was evidenced by lesser decreases in HSP60 expression and level of LC3-Ⅱ, suggesting Pb-induced mitophagy may be activated by the ER stress. Taken together, these findings provide a better understanding of Pb toxicity and suggest that Pb-induced ER stress may play a regulatory role in the upstream of mitophagy.
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Dopkins, Nicholas, Kiesha Wilson, Kathryn Miranda, Prakash S. Nagarkatti, and Mitzi Nagarkatti. "Efficacy of cannabidiol treatment in experimental MS is due to immunosuppressive activity of myeloid cells in CNS downregulating recruitment of CD4+ T cells, proinflammatory chemokines and gasdermin D expression." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 142.26. http://dx.doi.org/10.4049/jimmunol.204.supp.142.26.
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Abstract Cannabidiol (CBD) is a nonpsychoactive ingredient from Cannabis that has garnered attention in the medical community due to its anti-inflammatory properties and therapeutic potential. CBD has in particular become a popular alternative medicine among individuals with autoimmune disorders due to CBD lacking the side effects and costs associated with immunosuppressants. To better define how CBD inhibits inflammation, we studied the effects of orally administering CBD (20mg/kg) in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Using single cell RNA sequencing on cells isolated from the central nervous system (CNS) of EAE mice, we demonstrated that CBD treatment inhibits neuroinflammation by regulating gene expression and infiltration of myeloid cells. Within the resident and infiltrating myeloid cells of the CNS, there was decreased expression of inflammatory cytokines and chemokines (CXCL9, CXCL10, IL-18) associated with neuroinflammation and CD4+ T cell recruitment, pyroptosis initiators (gasdermin D; Gsdmd), oxide synthesizers (Arg1) and antigen presentation mediators (CD40) in CBD-treatment group. Additionally, CBD yielded an increase in the polymorphonuclear myeloid derived suppressor cells in the CNS, signifying immunotolerance induction at the site of inflammation. In the VEH treated mice, we found CD4+ T cells that express the receptor for IL-18 (IL-18r1) that are absent in CBD treated mice, suggesting CBD affects T cell activity via inhibition of myeloid cell activity. This data shows that CBD treatment ameliorates EAE by inhibiting infiltration, pro-inflammatory cytokine production, antigen presentation, T cell recruitment and pyroptosis of myeloid cells in the CNS.
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Zhuo, Xiaoneng, Shuji Shiozaki, Tsuneo Ogata, and Shosaku Horiuchi. "The Relationship between the Origin of Secondary Shoots on the Primary Shoot on the Induction of Tendrils and Inflorescenes, Signifying the End of the Transition Phase in V. ficifolia and Grape Vines." Engei Gakkai zasshi 72, no. 6 (2003): 539–45. http://dx.doi.org/10.2503/jjshs.72.539.
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Farooq, Zunaira, Muhammad Nouman Riaz, Muhammad Shoaib Farooq, Yifan Li, Huadong Wang, Mayra Ahmad, Jinxing Tu, et al. "Induction of Male Sterility by Targeted Mutation of a Restorer-of-Fertility Gene with CRISPR/Cas9-Mediated Genome Editing in Brassica napus L." Plants 11, no. 24 (December 13, 2022): 3501. http://dx.doi.org/10.3390/plants11243501.
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Brassica napus L. (canola, oil seed rape) is one of the world’s most important oil seed crops. In the last four decades, the discovery of cytoplasmic male-sterility (CMS) systems and the restoration of fertility (Rf) genes in B. napus has improved the crop traits by heterosis. The homologs of Rf genes, known as the restoration of fertility-like (RFL) genes, have also gained importance because of their similarities with Rf genes. Such as a high non-synonymous/synonymous codon replacement ratio (dN/dS), autonomous gene duplications, and a possible engrossment in fertility restoration. B. napus contains 53 RFL genes on chromosomes A9 and C8. Our research aims to study the function of BnaRFL11 in fertility restoration using the CRISPR/Cas9 genome editing technique. A total of 88/108 (81.48%) T0 lines, and for T1, 110/145 (75%) lines carried T-DNA insertions. Stable mutations were detected in the T0 and T1 generations, with an average allelic mutation transmission rate of 81%. We used CRISPR-P software to detect off-target 50 plants sequenced from the T0 generation that showed no off-target mutation, signifying that if the designed sgRNA is specific for the target, the off-target effects are negligible. We also concluded that the mutagenic competence of the designed sgRNAs mediated by U6-26 and U6-29 ranged widely from 31% to 96%. The phenotypic analysis of bnarfl11 revealed defects in the floral structure, leaf size, branch number, and seed production. We discovered a significant difference between the sterile line and fertile line flower development after using a stereomicroscope and scanning electron microscope. The pollen visibility test showed that the pollen grain had utterly degenerated. The cytological observations of homozygous mutant plants showed an anther abortion stage similar to nap-CMS, with a Orf222, Orf139, Ap3, and nad5c gene upregulation. The bnarfl11 shows vegetative defects, including fewer branches and a reduced leaf size, suggesting that PPR-encoding genes are essential for the plants’ vegetative and reproductive growth. Our results demonstrated that BnaRFL11 has a possible role in fertility restoration. The current study’s findings suggest that CRISPR/Cas9 mutations may divulge the functions of genes in polyploid species and provide agronomically desirable traits through a targeted mutation.
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Pefanis, Gerasimos, Nikolaos Maniotis, Aikaterini-Rafailia Tsiapla, Antonios Makridis, Theodoros Samaras, and Mavroeidis Angelakeris. "Numerical Simulation of Temperature Variations during the Application of Safety Protocols in Magnetic Particle Hyperthermia." Nanomaterials 12, no. 3 (February 6, 2022): 554. http://dx.doi.org/10.3390/nano12030554.
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Unavoidably, magnetic particle hyperthermia is limited by the unwanted heating of the neighboring healthy tissues, due to the generation of eddy currents. Eddy currents naturally occur, due to the applied alternating magnetic field, which is used to excite the nanoparticles in the tumor and, therefore, restrict treatment efficiency in clinical application. In this work, we present two simply applicable methods for reducing the heating of healthy tissues by simultaneously keeping the heating of cancer tissue, due to magnetic nanoparticles, at an adequate level. The first method involves moving the induction coil relative to the phantom tissue during the exposure. More specifically, the coil is moving symmetrically—left and right relative to the specimen—in a bidirectional fashion. In this case, the impact of the maximum distance (2–8 cm) between the coil and the phantom is investigated. In the second method, the magnetic field is applied intermittently (in an ON/OFF pulsed mode), instead of the continuous field mode usually employed. The parameters of the intermittent field mode, such as the time intervals (ON time and OFF time) and field amplitude, are optimized based on the numerical assessment of temperature increase in healthy tissue and cancer tissue phantoms. Different ON and OFF times were tested in the range of 25–100 s and 50–200 s, respectively, and under variable field amplitudes (45–70 mT). In all the protocols studied here, the main goal is to generate inside the cancer tissue phantom the maximum temperature increase, possible (preferably within the magnetic hyperthermia window of 4–8 °C), while restricting the temperature increase in the healthy tissue phantom to below 4 °C, signifying eddy current mitigation.
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Lucas, Edgar, David Campos-Gaona, and Olimpo Anaya-Lara. "Assessing the Impact of DFIG Synthetic Inertia Provision on Power System Small-Signal Stability." Energies 12, no. 18 (September 6, 2019): 3440. http://dx.doi.org/10.3390/en12183440.
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Synthetic inertia provision through the control of doubly-fed induction generator (DFIG) wind turbines is an effective means of providing frequency support to the wider electrical network. There are numerous control topologies to achieve this, many of which work by making modifications to the DFIG power controller and introducing additional loops to relate active power to electrical frequency. How these many controller designs compare to one-another in terms of their contribution to frequency response is a much studied topic, but perhaps less studied is their effect on the small-signal stability of the system. The concept of small-signal stability in the context of a power system is the ability to maintain synchronism when subjected to small disturbances, such as those associated with a change in load or a loss of generation. Amendments made to the control system of a large-scale wind farm will inevitably have an effect on the system as a whole, and by making a DFIG wind turbine behave more like a synchronous generator, which synthetic inertia provision does, may incur consequences relating to electromechanical oscillations between generating units. This work compares the implications of two prominent synthetic inertia controllers of varying complexity and their effect on small-signal stability. Eigenvalue analysis is conducted to highlight the key information relating to electromechanical modes between generators for the two control strategies, with a focus on how these affect the damping ratios. It is shown that as the synthetic inertia controller becomes both more complex and more effective, the damping ratio of the electromechanical modes is reduced, signifying a decreased system stability.
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de Jesus Menezes-Filho, Noélio, Cleide dos Santos Souza, Tereza Cristina Silva Costa, Victor Diógenes Amaral da Silva, Cátia Suse de Oliveira Ribeiro, Marizeth Liborio Barreiros, Jose Fernando Oliveira Costa, Jorge Mauricio David, Juceni P. L. David, and Silvia Lima Costa. "Cytotoxicity of the Diterpene 14-O-Methyl-ryanodanol from Erythroxylum passerinum in an Astrocytic Cells Model." Natural Product Communications 9, no. 9 (September 2014): 1934578X1400900. http://dx.doi.org/10.1177/1934578x1400900906.
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Plant secondary metabolites, such as, specifically, alkaloids and terpenes, may present psychoactive properties that modify the function of the central nervous system (CNS) and induce neurotoxicity. Neurotoxicity involves the response of glial cells, mainly astrocytes, which play a fundamental role in the control of homeostasis of the CNS. Some Erythroxylum species are indigenous to the state of Bahia in Brazil. This study investigated the cytotoxic activity of the diterpene AEP-1, extracted from the fruit of E. passerinum in a GL-15 cell line, astrocytic, glial cells model. The effects on cell viability, analyzed by the MTT assay, demonstrated a dose-dependent cytotoxic effect, with maximum effect at 500 μg/mL of AEP-1, and with a reduction of about 40 and 47% on cellular viability after 24 h and 72 h treatment, respectively. Evidence for induction of apoptosis by AEP-1 was first obtained when GL-15 glial cells were incubated with 250 μg/mL AEP-1 causing reniform and/or pyknotic nuclei and apoptotic bodies revealed by chromatin staining with Hoechst 33258. Increase in DNA fragmentation was also observed by comet assays in cells incubated with 500 μg/mL of AEP-1. Moreover, cells exposed to a sub toxic dose of AEP-1 (250 μg/mL) showed significant changes in morphology – contraction of the cytoplasm and expansion of cellular projections – signifying the presence of astrocytic cytoskeletal protein and glial fibrillary acidic protein (GFAP). These findings indicated astrocytic cells as the target for terpene AEP-1 and suggest the involvement of glial cells with psychoactive symptoms observed in humans and animals after consumption of fruits of plants of the genus Erythroxylum.
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Pasricha, Gunisha, Sanjay Mukherjee, and Alok K. Chakrabarti. "Apoptotic and Early Innate Immune Responses to PB1-F2 Protein of Influenza A Viruses Belonging to Different Subtypes in Human Lung Epithelial A549 Cells." Advances in Virology 2018 (December 31, 2018): 1–12. http://dx.doi.org/10.1155/2018/5057184.
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PB1-F2 is a multifunctional protein and contributes to the pathogenicity of influenza A viruses. PB1-F2 is known to have strain and cell specific functions. In this study we have investigated the apoptotic and inflammatory responses of PB1-F2 protein from influenza viruses of diverse pathogenicities in A549 lung epithelial cells. Overexpression of PB1-F2 resulted in apoptosis and heightened inflammatory response in A549 cells. Comparison revealed that the response varied with each subtype. PB1-F2 protein from highly pathogenic H5N1 virus induced least apoptosis but maximum inflammatory response. Results indicated that apoptosis was mediated through death receptor ligands TNFα and TRAIL via Caspase 8 activation. Significant induction of cytokines/chemokines CXCL10, CCL5, CCL2, IFNα, and IL-6 was noted in A549 cells transfected with PB1-F2 gene construct of 2008 West Bengal H5N1 virus (H5N1-WB). On the contrary, PB1-F2 construct from 2007 highly pathogenic H5N1 isolate (H5N1-M) with truncated N-terminal region did not evoke as exuberant inflammatory response as the other H5N1-WB with full length PB1-F2, signifying the importance of N-terminal region of PB1-F2. Sequence analysis revealed that PB1-F2 proteins derived from different influenza viruses varied at multiple amino acid positions. The secondary structure prediction showed each of the PB1-F2 proteins had distinct helix-loop-helix structure. Thus, our data substantiate the notion that the contribution of PB1-F2 to influenza pathogenicity is greatly strain specific and involves multiple host factors. This data demonstrates that PB1-F2 protein of influenza A virus, when expressed independently is minimally apoptotic and strongly influences the early host response in A549 cells.
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Flowers, Christopher, Iris Isufi, Alex Francisco Herrera, Craig Okada, Elizabeth H. Cull, Bela Kis, Jorge Chaves, et al. "Intratumoral G100 to induce systemic immune responses and abscopal tumor regression in patients with follicular lymphoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 7537. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.7537.
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7537 Background: Follicular lymphoma (FL) is an incurable malignancy with patients (pts) ultimately relapsing following standard therapies. Active immunotherapy has the potential to induce life-long host anti-tumor immunity and disease control. G100 consists of glucopyranosyl lipid-A (GLA), a TLR-4 agonist in a specific formulation. Preclinically, G100 activates dendritic cells, T cells and NK cells, and triggers systemic anti-tumor immunity. In Merkel Cell carcinoma pts, G100 administered intratumorally (IT) induced tumor inflammation and responses including a CR after G100 alone. This is the first study of G100 IT in pts with NHL. Methods: Previously treated or naïve pts with FL with an injectable tumor site and distal sites of disease were eligible. In Part 1, G100 cohorts of 5 or 10µg were enrolled in a 3+3 design, followed by a large tumor ( > 4cm) cohort at 20µg. Pts received 6-9 doses of G100 IT ~qwk after radiation (RT, 2 Gy x2 doses) to the lesion. A 2nd course of G100 could be given without RT to an additional site. Results: As of 31Dec16, all 9 pts in Part 1 dose escalation (3 pts each at 5, 10, or 20 µg/dose) were evaluable for safety and efficacy. An additional 13 pts at 10µg/dose were included in the safety analysis only. No G100-related DLTs or SAEs were observed at any dose level. Of 22 safety pts, all G100 related AEs were grade 1/2 and none occurred in > 2 pts. Tumor biopsies following G100 demonstrated diffuse infiltration of CD8+ T cells in 5/5 pts and T cell repertoire analyses indicated an increased frequency of clonal tumor infiltrating lymphocytes (TILs). Best responses include: 4 PRs (45%), 3 SDs (33%) and 2 pending (22%). Of the 4 PR pts, tumor regression ranged 58-89% including up to 56% shrinkage of abscopal (distal) sites. Conclusions: G100 IT was safe, well-tolerated, induced CD8+ T cell infiltration and expansion of TIL clones. G100/RT treated and abscopal lesion regressions were observed signifying the induction or boosting of systemic anti-tumor immunity. The induction of immune responses, favorable safety profile and clinical activity indicate that G100 IT is an active agent that warrants further investigation. Part 2 enrollment continues with randomization to G100/RT ± pembrolizumab. Clinical trial information: NCT02501473.
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Eren, Barış, Aras Türkoğlu, Kamil Haliloğlu, Fatih Demirel, Kamila Nowosad, Güller Özkan, Gniewko Niedbała, Alireza Pour-Aboughadareh, Henryk Bujak, and Jan Bocianowski. "Investigation of the Influence of Polyamines on Mature Embryo Culture and DNA Methylation of Wheat (Triticum aestivum L.) Using the Machine Learning Algorithm Method." Plants 12, no. 18 (September 13, 2023): 3261. http://dx.doi.org/10.3390/plants12183261.
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Numerous factors can impact the efficiency of callus formation and in vitro regeneration in wheat cultures through the introduction of exogenous polyamines (PAs). The present study aimed to investigate in vitro plant regeneration and DNA methylation patterns utilizing the inter-primer binding site (iPBS) retrotransposon and coupled restriction enzyme digestion–iPBS (CRED–iPBS) methods in wheat. This investigation involved the application of distinct types of PAs (Put: putrescine, Spd: spermidine, and Spm: spermine) at varying concentrations (0, 0.5, 1, and 1.5 mM). The subsequent outcomes were subjected to predictive modeling using diverse machine learning (ML) algorithms. Based on the specific polyamine type and concentration utilized, the results indicated that 1 mM Put and Spd were the most favorable PAs for supporting endosperm-associated mature embryos. Employing an epigenetic approach, Put at concentrations of 0.5 and 1.5 mM exhibited the highest levels of genomic template stability (GTS) (73.9%). Elevated Spd levels correlated with DNA hypermethylation while reduced Spm levels were linked to DNA hypomethylation. The in vitro and epigenetic characteristics were predicted using ML techniques such as the support vector machine (SVM), extreme gradient boosting (XGBoost), and random forest (RF) models. These models were employed to establish relationships between input variables (PAs, concentration, GTS rates, Msp I polymorphism, and Hpa II polymorphism) and output parameters (in vitro measurements). This comparative analysis aimed to evaluate the performance of the models and interpret the generated data. The outcomes demonstrated that the XGBoost method exhibited the highest performance scores for callus induction (CI%), regeneration efficiency (RE), and the number of plantlets (NP), with R2 scores explaining 38.3%, 73.8%, and 85.3% of the variances, respectively. Additionally, the RF algorithm explained 41.5% of the total variance and showcased superior efficacy in terms of embryogenic callus induction (ECI%). Furthermore, the SVM model, which provided the most robust statistics for responding embryogenic calluses (RECs%), yielded an R2 value of 84.1%, signifying its ability to account for a substantial portion of the total variance present in the data. In summary, this study exemplifies the application of diverse ML models to the cultivation of mature wheat embryos in the presence of various exogenous PAs and concentrations. Additionally, it explores the impact of polymorphic variations in the CRED–iPBS profile and DNA methylation on epigenetic changes, thereby contributing to a comprehensive understanding of these regulatory mechanisms.
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Ahmad, Bilal, Jin Yao, Songlin Zhang, Xingmei Li, Xiuming Zhang, Vivek Yadav, and Xiping Wang. "Genome-Wide Characterization and Expression Profiling of GASA Genes during Different Stages of Seed Development in Grapevine (Vitis vinifera L.) Predict Their Involvement in Seed Development." International Journal of Molecular Sciences 21, no. 3 (February 6, 2020): 1088. http://dx.doi.org/10.3390/ijms21031088.
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Members of the plant-specific GASA (gibberellic acid-stimulated Arabidopsis) gene family have multiple potential roles in plant growth and development, particularly in flower induction and seed development. However, limited information is available about the functions of these genes in fruit plants, particularly in grapes. We identified 14 GASA genes in grapevine (Vitis vinifera L.) and performed comprehensive bioinformatics and expression analyses. In the bioinformatics analysis, the locations of genes on chromosomes, physiochemical properties of proteins, protein structure, and subcellular positions were described. We evaluated GASA proteins in terms of domain structure, exon-intron distribution, motif arrangements, promoter analysis, phylogenetic, and evolutionary history. According to the results, the GASA domain is conserved in all proteins and the proteins are divided into three well-conserved subgroups. Synteny analysis proposed that segmental and tandem duplication have played a role in the expansion of the GASA gene family in grapes, and duplicated gene pairs have negative selection pressure. Most of the proteins were predicted to be in the extracellular region, chloroplasts, and the vacuole. In silico promoter analysis suggested that the GASA genes may influence different hormone signaling pathways and stress-related mechanisms. Additionally, we performed a comparison of the expression between seedless (Thompson seedless) and seeded (Red globe) cultivars in different plant parts, including the ovule during different stages of development. Furthermore, some genes were differentially expressed in different tissues, signifying their role in grapevine growth and development. Several genes (VvGASA2 and 7) showed different expression levels in later phases of seed development in Red globe and Thompson seedless, suggesting their involvement in seed development. Our study presents the first genome-wide identification and expression profiling of grapevine GASA genes and provides the basis for functional characterization of GASA genes in grapes. We surmise that this information may provide new potential resources for the molecular breeding of grapes.
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Staskiewicz, Anna, Erica Wong, Michael Tucker, Riya Farhin, Jonathan Park, Rana Saade, Tina Alkhazali, Tu Dang, and Xinyu Wang. "Cytotoxic and Apoptotic Effects of Pinostilbene and Bortezomib Combination Treatment on Human Multiple Myeloma Cells." International Journal of Molecular Sciences 24, no. 16 (August 9, 2023): 12590. http://dx.doi.org/10.3390/ijms241612590.
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Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow characterized by bone lesions, hypercalcemia, anemia, and renal failure. Bortezomib (BTZ), a common treatment for MM, is a proteasome inhibitor that induces apoptosis in MM cells. However, high doses of BTZ can be very toxic, signifying a need for a synergistic drug combination to improve treatment efficacy. Resveratrol (RES), a phenolic compound found in grapes, has been shown to inhibit MM cell growth. We sought to identify a synergistic combination of BTZ with a RES derivative and analyze the effects on reducing viability and inducing apoptosis in human MM cells. BTZ as well as RES and its derivatives pinostilbene (PIN) and piceatannol (PIC) decreased MM cell viability in a dose- and time-dependent manner and increased expression of cleaved proapoptotic proteins poly(ADP-ribose) polymerase 1 (PARP1) and caspase-3 in a dose-dependent manner. The combination of 5 nM BTZ and 5 μM PIN was identified to have synergistic cytotoxic effects in MM RPMI 8226 cells. MM RPMI 8226 cells treated with this combination for 24 h showed increased cleaved PARP1 and caspase-3 expression and higher percentages of apoptotic cells versus cells treated with the individual compounds alone. The treatment also showed increased apoptosis induction in MM RPMI 8226 cells co-cultured with human bone marrow stromal HS-5 cells in a Transwell model used to mimic the bone marrow microenvironment. Expression of oxidative stress defense proteins (catalase, thioredoxin, and superoxide dismutase) in RPMI 8226 cells were reduced after 24 h treatment, and cytotoxic effects of the treatment were ameliorated by antioxidant N-acetylcysteine (NAC), suggesting the treatment impacts antioxidant levels in RPMI 8226 cells. Our results suggest that this combination of BTZ and PIN decreases MM cell viability synergistically by inducing apoptosis and oxidative stress in MM cells.
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Suzuki, Sakiko, Nathan A. Manalo, and Glen D. Raffel. "Ott1(Rbm15) Regulates p53 Levels during Oncogenic and Proliferative Stress." Blood 126, no. 23 (December 3, 2015): 1189. http://dx.doi.org/10.1182/blood.v126.23.1189.1189.
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Abstract Ott1(Rbm15) is essential for engraftment and maintaining hematopoietic stem cell (HSC) quiescence during proliferative stress; therefore we sought to establish whether Ott1 has a regulatory role within the cell cycle. Ott1 knockout (KO) E14.5 murine embryonic fibroblasts (MEFs) were analyzed using BrdU labelling and demonstrated a higher basal proliferative rate. However, when subjected to oncogenic stress induced by infection with a constitutively active N-Ras expressing retrovirus, Ott1-deleted MEFs undergo immortalization and morphologic transformation in contrast to wild type (WT) MEFs which undergo senescence. Oncogene-induced senescence is a p53-facilitated process. P53 protein levels were shown by western blot to decrease in Ras-infected Ott1 KO MEFs rather than increase as observed in WT Ras-infected MEFs. Consistent with this finding, p16Ink4a, which is a transcriptional target of p53, is not upregulated in Ras-infected Ott1 KO MEFs. Gamma irradiation was still able to induce p53 in Ott1 KO MEFS, demonstrating Ott1 regulation of p53 is specific to the oncogenic stress pathway, but not the DNA damage pathway. Measurement of p53 mRNA levels in Ras-infected Ott1 KO MEFs showed a modest increase compared to WT, indicating the p53 protein decrease must occur at a post-transcriptional level. Classical p53 induction by oncogenic stress occurs through inhibition of ubiquitin-mediated degradation of p53 by ligases such as Mdm2 and Mdm4. To determine why Ras induction of p53 is defective in Ott1 KO MEFS, Ras-infected cells were incubated with the proteasome inhibitor, MG132, which was able to rescue p53 induction, implicating a ubiquitination-dependent mechanism. Furthermore, incubation with Nutlin3, an Mdm2-specific inhibitor, also showed significant rescue of p53 induction, signifying Ott1 is required for Mdm2-mediated degradation of p53 during oncogenic stress. P53 has an essential, non-apoptotic role in HSC function and has also been shown to help maintain HSC quiescence and self-renewal. We previously identified an Ott1-dependent mechanism for down-regulating Thrombopoietin response via its receptor Mpl in Ott1 KO HSCs through expression of a dominant negative alternatively spliced isoform, Mpl-TR. Although Mpl-TR expression is sufficient to reduce Mpl signaling and competitive repopulation in Ott1 KO HSCs, full length Mpl alone is unable to rescue engraftment of Ott1 -deleted HSCs suggesting Ott1 has other critical targets. Based on the Ott1-dependence of p53 function in MEFs, we hypothesized a similar dysfunction of the p53 pathway exists in Ott1 KO HSCs undergoing proliferative stress. Ott1 KO and WT HSCs were analyzed before and after incubation in a cytokine-rich medium to stimulate proliferation. At baseline, Ott1 KO HSCs have similar p53 protein levels as WT HSCs. However, after cytokine stimulation, Ott1 KO HSCs shift into active cell cycle more readily and now demonstrate a significant decrease in p53 protein levels as measured by intracellular flow cytometry. In summary, Ott1 is required for p53 response during oncogenic stress via inhibition of Mdm2. Ott1 is similarly required to maintain p53 levels during proliferative stress in HSCs and may thereby promote quiescence and self-renewal. Moreover, OTT1 is the 5' fusion partner in the chimeric OTT1-MAL (RBM15-MKL1) product in t(1;22)-associated acute megakaryocytic leukemia, raising the possibility that dysregulation of p53 pathways may contribute to the pathogenesis of t(1;22)-derived leukemias. Disclosures No relevant conflicts of interest to declare.
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Kapoor, Sabeeta, and Roderick H. Dashwood. "Abstract 5712: Dietary polyphenols as BRD7 and 9 inhibitors for cancer interception." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5712. http://dx.doi.org/10.1158/1538-7445.am2022-5712.
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Abstract Introduction Epigenetic mechanisms play an important role in the initiation and advancement of colorectal cancer (CRC) and other malignancies due, in part, to deregulated bromodomain (BRD) functions1,2. We examined compounds from natural sources as BRD7/9 inhibitors, seeking lead candidates outside of the widely studied bromodomain and extraterminal (BET) family3. Methods As reported4,5, docking in silico involved STRAP and AutoDock Vina, ligand-protein interactions employed PDBePISA and LPC/CSU, and BROMOscan®-Bromodomain arrays were used to screen for BRD7/9 interacting compounds. BRD7/9 inhibitors also were assessed by isothermal titration calorimetry (ITC) and by anticancer activities in human colon cancer cells. Results Docking in silico identified several dietary polyphenols as potential BRD7/9 inhibitors, with binding energies ≤ -8.0 kcal/mol. BROMOscan® and ITC experiments prioritized aspalathin, orientin, epigallocatechin-3-gallate, quercetin and equol for further investigation. Treatment with selected polyphenols mimicked BRD7/9 siRNA-mediated knockdown in reducing colon cancer cell viability and inhibiting colony formation, leading to DNA damage and apoptosis induction. Normal colonic epithelial cells were unaffected by the treatments, signifying cancer-specific targeting. These findings suggest that dietary polyphenols can recognize and target BRD7/9 proteins for potential cancer interception. Acknowledgements Research supported in part by NCI grant CA122959, the John S. Dunn Foundation, and a Chancellor's Research Initiative.1)Jung G et al., Nat Rev Gastroenterol Hepatol 2020;17:111-130. 2)Fujisawa T, Filippakopoulos P. Nat Rev Mol Cell Biol 2017;18:246-262.3)Damiani E et al., J Cancer Prev 2020;25:189-203. 4)Rajendran P et al., Cancer Res 2019;79:918-927. 5)Kapoor S et al., Cancers (Basel) 2021;13:1438. Citation Format: Sabeeta Kapoor, Roderick H. Dashwood. Dietary polyphenols as BRD7 and 9 inhibitors for cancer interception [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5712.
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Zhang, Jie, and Ramalingam Kowsalya. "Daidzein Ameliorates Cerebral Ischemic-reperfusion Induced Neuroinflammation in Wistar Rats via Inhibiting NF-κB Signaling Pathway." Pharmacognosy Magazine 19, no. 1 (January 18, 2023): 85–96. http://dx.doi.org/10.1177/09731296221137378.
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Background Cerebral ischemia is a condition of acute brain damage due to the depletion of oxygenated blood supply to cerebral tissues. Daidzein is an isoflavonoid predominantly present in soya, Pueraria species, and red cloves. Traditional Chinese medicine utilizes daidzein to alleviate diseases such as inflammation, hyperglycemia, gastric diseases, allergies and aches. The neuroprotective effect of daidzein on cerebral ischemic conditions and its mechanism of action was not yet elucidated. Materials and Methods 24 healthy male adult Wistar rats were grouped into four and the control rats were sham-operated, cerebral ischemic-reperfusion induced rats subjected to middle cerebral artery occlusion (MCAO). Low- and high-dose daidzein rats were treated with 25 and 50 mg/kg daidzein respectively for 7 consecutive days before the induction of cerebral ischemic reperfusion. On completion of treatment, the rats were assessed for neurological deficit scoring and then euthanized for further analysis. The percentage of brain water content and cerebral infarct was evaluated. The ability of daidzein on preventing oxidative stress-induced damage was assessed by quantifying lipid peroxidation and antioxidant levels. The neuroprotective Daidzein was evaluated by measuring the acetylcholinesterase activity and brain ATP levels. The anti-inflammatory role of Daidzein was measured by quantifying the nitric oxide (NO) and inflammatory cytokines. Further, the anti-ischemic role of Daidzein was confirmed by estimating nuclear factor-kappa B (NF-κB) p65 and Caspase 3 levels. Results Daidzein treatment significantly prevented brain edema and cerebral infarction and neurological deficit in cerebral I/R injured rats. It also scavenged the free radicals and prevented the decline in antioxidant levels of ischemic rats. Daidzein decreased the acetylcholinesterase activity, NO, and inflammatory and significantly increased the brain ATP levels signifying its neuroprotective role in ischemic-induced rats. The reduction in the levels of NF-κB p65 and Caspase 3 confirms daidzein prevents neuroinflammation and neuronal apoptosis in ischemic rats. Conclusion Overall our analysis confirms daidzein is a potent neuroprotective drug which can effectively inhibit postischemic complications.
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Rifkin, Robert M., Rafat Abonour, Brian G. M. Durie, Cristina J. Gasparetto, Sundar Jagannath, Mohit Narang, Jatin J. Shah, et al. "Treatment Patterns from 2009 to 2015 in Patients with Newly Diagnosed Multiple Myeloma in the United States: A Report from the Connect® MM Registry." Blood 128, no. 22 (December 2, 2016): 4489. http://dx.doi.org/10.1182/blood.v128.22.4489.4489.
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Abstract Introduction: Between 2009 and 2015, use of novel therapies (immunomodulating drugs and proteasome inhibitors) in multiple myeloma (MM) increased. Regimens initiated during this time frame may help project near-term future treatment patterns. Connect® MM is the first and largest prospective, observational, US-based, multicenter disease registry designed to characterize treatment patterns and outcomes for patients (pts) with newly diagnosed MM (NDMM). Pts with NDMM were enrolled in 2 sequential cohorts from Sep 2009 to Apr 2016. This noninterventional registry did not prescribe or limit therapy choices. Study sites represented all census regions, with 89% and 11% split between community and academic sites, respectively. This allowed a reasonable generalizability to patterns for the US. Methods: Connect® MM enrollment was initiated in Sep 2009 at 250 community and academic sites. Pts were enrolled within 2 months of diagnosis. Cohort 1 enrolled 1493 NDMM pts from Sep 2009 to Dec 2011, and Cohort 2 enrolled 1518 NDMM pts from Dec 2012 to Apr 2016. Data were collected at a baseline visit and quarterly visits thereafter until death or discontinuation. The current analysis was conducted for the population of treated pts (N=2848) as of May 2016. This study examined recorded treatment choice of first-line regimen, maintenance therapy, and second-line regimen in 6-month intervals. Trends in regimens were graphically represented using "Tepee" plots (Srinivasan, Shankar. Resource Tepee. Patent US 7,495,673 B1. 24 Feb 2009). Briefly, all pts who initiated treatment during each 6-month interval are represented horizontally, with each horizontal line indicating 100% of all treatment used in that period. The regimens are represented by gray shading with wider bands signifying the more frequently used regimens at each time interval. Results: Median follow‐up for all pts was 39.3 months (0.03‐78.4) in Cohort 1 and 15.4 months (0.2-40.1) in Cohort 2. For the treated population, the median age was 67 years (range 24‐94), 58% were male, 83% were white, and 38% of those reporting International Staging System stage had stage III MM. By US geographical region, 329 (11.6%) pts were from the Northeast, 1036 (36.4%) from the Midwest, 1117 (39.2%) from the South, 360 (12.6%) from the West, 4 (0.1%) from Puerto Rico, and 2 missing (0.05%). Most pts (2285; 80.2%) were from community sites, and 397 (13.9%) were from academic sites with the remaining from government sites. A total of 1416 (47.4%) reported an intent to transplant (stem cell transplant [SCT]) at the initiation of therapy. A total of 666 (25.8%) have progressed and entered second line. Tepee plots of treatment patterns for start of induction for those pts with and without SCT intent are provided in Figure 1A and 1B, respectively. The year 2012 does not feature in these induction plots, as this period corresponds to a time when pts were not enrolled-Cohort 1 had been completed and Cohort 2 had not yet opened. The 4 most common induction regimens for SCT intent, from left to right, in order of decreasing frequency of use, were lenalidomide (R), bortezomib (V), dexamethasone (D) combined (RVD); VD; cyclophosphamide plus VD (CyBorD); and RD. The 5 most common induction regimens for those without SCT intent, from left to right, in order of decreasing frequency of use, were VD, RD, RVD, CyBorD, and V. Triplet therapy in first-line induction pts increased in frequency from 2009 to 2014. The 4 most frequent maintenance regimens for those with SCT intent were R monotherapy, V monotherapy, RD, and RVD. The 4 most common maintenance regimens for pts who did not intend to receive SCT were R monotherapy, RD, VD, and V monotherapy. The most prevalent regimens in the second line were VD, RD, V, and RVD. Additional graphs including treatment patterns by age group (≤ 70 vs > 70 years) and maintenance by conduct of first-line SCT will be presented. Conclusions: Our work utilizes Tepee plots to outline induction and maintenance treatment patterns over time, for both SCT and non-SCT intent pts, using the largest, prospective, noninterventional registry study in the US. Triplet therapy use increased in the time period studied, with RVD being the most frequently used triplet for pts with or without SCT intent. The most common maintenance regimens included R as monotherapy or in combination. Disclosures Rifkin: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen/ONYX: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Gasparetto:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria. Jagannath:Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Terebelo:Celgene: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene: Consultancy. Kitali:Celgene: Employment, Equity Ownership. Zafar:Celgene: Employment. Srinivasan:Celgene: Employment; Individual Patent: Patents & Royalties: US7,495,673B1 Used for MM-Connect Treatment Patterns Abstract.. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Gilzad-Kohan, Hamed, Shabnam Sani, and Mehdi Boroujerdi. "Calcitriol Reverses Induced Expression of Efflux Proteins and Potentiates Cytotoxic Activity of Gemcitabine in Capan-2 Pancreatic Cancer Cells." Journal of Pharmacy & Pharmaceutical Sciences 20 (August 24, 2017): 295. http://dx.doi.org/10.18433/j37w7r.
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Purpose. Efflux and influx proteins play a major role in chemo-resistance by affecting the net cellular uptake of anti-cancer drugs. Hence, alteration of the efflux and influx protein expression may result in variations of chemotherapeutics uptake and consequently cell death rate. The present study investigated the effects of pre-treatment of capan-2 pancreatic cancer cells with calcitriol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) or silibinin on the induction of three major efflux proteins and the main gemcitabine influx protein. The influence of the pre-treatments on the net cellular uptake of gemcitabine, total ATPase activity, and cell death rate were also evaluated. Methods. Capan-2 pancreatic cancer cells were pre-treated for 24 h with calcitriol, BHT, BHA, or silibinin, followed by gemcitabine treatment. The concentration of gemcitabine was quantified using ultra-performance liquid chromatography (UPLC). Real-time polymerase chain reaction (RT-PCR) was utilized in order to investigate the expression of the mRNAs. The expression of the proteins was assessed using western blotting. Measurement of the ATPase activity was conducted utilizing a colorimetric method and viability of the cells was determined using a luminescent cell viability assay. Results. Protein expression studies showed that BHT, silibinin, and BHA increased expression of the efflux proteins and decreased the overall uptake of gemcitabine, whereas calcitriol significantly inhibited expression of the efflux proteins and increased gemcitabine uptake. Expression of specific mRNAs correlated reasonably well with the levels of corresponding proteins. Additionally, the expression of efflux proteins and ATPase activity were well correlated, signifying that the induced efflux proteins are functionally active. Moreover, pre-treatment with calcitriol resulted in a significant increase in cell death with gemcitabine treatment, whereas, BHA significantly reduced the cell death rate. On the other hand, pre-treatment with BHT and silibinin had no significant effect on the cell death rate. Conclusions. Pre-treatment of the pancreatic cancer cells with calcitriol significantly increased gemcitabine cellular uptake and consequently decreased cell viability after treatment with gemcitabine, whereas BHA significantly reduced gemcitabine uptake and decreased cell death rate, which were at least partially attributed to the alteration of expression of efflux and influx proteins. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Erikha, Fajar. "PENANDAAN DAN PEMAKNAAN TERITORIAL DI KANTIN SASTRA BAGI MAHASISWA FAKULTAS ILMU PENGETAHUAN BUDAYA UNIVERSITAS INDONESIA." Paradigma, Jurnal Kajian Budaya 7, no. 1 (July 4, 2018): 50. http://dx.doi.org/10.17510/paradigma.v7i1.139.
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<p>This study explores the phenomenon of marking (signifying) and meaning of territorial at Kantin Sastra (Kansas) by undergraduate students of Fakultas Ilmu Pengetahuan Budaya Universitas Indonesia. Territory as a social space is formed through a process of semiosis preceded sensory knowing in identifying signs, repeatedly making representations in cognition that become the signifying order of the cultural semiotic on some students. Research using micro semiotic perspective and trichotomy of signs by Charles Sander Peirce. Through micro semiotic perspective, a number of particular findings will be analyzed to get a synthesis (inductive), whereas the approach of Peirce perspective explains the signs through the trichotomies: representamen represented through qualisigns, sinsigns, and legisigns; representation, represented by icons, indexes, and symbols; interpretant represented by rhemes, dicisigns, and arguments. As a result, there is a territorial signifying and meaning of Kansas by the undergraduate student of Fakultas Ilmu Pengetahuan Budaya Universitas Indonesia.</p>
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Wilkinson, Emma A., Tong Wu, Gayoung Park, Yan-Hong Cui, Chuan He, and Yu-Ying He. "Abstract 227: Kethoxal-assisted single-stranded DNA sequencing (KAS-seq) reveals dynamic and temporal changes in transcription in response to UVB exposure." Cancer Research 82, no. 12_Supplement (June 15, 2022): 227. http://dx.doi.org/10.1158/1538-7445.am2022-227.
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Abstract Skin cancer is the most common form of cancer, with over 5 million cases reported in 2021. UVB exposure derived from sunlight is the major carcinogenic driver of skin cancer and poses a major public health risk. In response to UVB exposure, keratinocytes must activate DNA repair pathways to avoid mutagenesis. In addition to DNA repair pathways, cells initiate well-coordinated DNA damage response pathways to facilitate the repair process, including arresting global transcription. Here we report the use of kethoxal-assisted single-strand DNA-Sequencing (KAS-Seq) technology to profile the transcriptional dynamics that underlie the DNA damage response upon UVB exposure. Mechanistically, KAS-Seq involves the addition of an azide-tagged kethoxal group (N3-kethoxal) to DNA samples, which then reacts with guanines on single-stranded DNA (ssDNA). A “KAS signal” is therefore only obtained when DNA is unwound, allowing the N3-kethoxal reaction with accessible guanines to occur. Accordingly, in response to DNA damage, DNA can form ssDNA bubbles in order to facilitate DNA damage recognition and repair processes. KAS-Seq is therefore a suitable method to profile the transcriptional dynamics that occur in response to UVB-induced DNA damage. Here we show that UVB exposure in normal human keratinocytes (NHEK) cells induces a temporal and dynamic reprogramming in transcription using KAS-Seq. In terms of global transcription, our data show that the greatest loss of KAS signal occurs rapidly between 30mins and 3hrs post-UVB exposure, signifying transcriptional arrest. Interestingly, KAS signal is regained between 6-24hrs post-UVB, which is representative of a transition towards transcriptional recovery and induction of DNA damage processes. Furthermore, a more discrete and targeted analysis shows that the gain and loss of KAS signals primarily occur within the gene body, followed by promoter and intergenic regions. Overall, our data shows that transcriptional control in response to UVB-induced DNA damage is both dynamic and temporal. Further analysis is required to identify which transcriptional phenotype (transcriptional arrest or transcriptional recovery) is the most deleterious to the cell and DNA damage repair processes when disrupted. Additionally, we aim to further elucidate the molecular mechanisms that underlie these global changes in transcription, which will provide expanded insights into the wide-ranging oncogenic mechanisms that underlie UVB exposure. Citation Format: Emma A. Wilkinson, Tong Wu, Gayoung Park, Yan-Hong Cui, Chuan He, Yu-Ying He. Kethoxal-assisted single-stranded DNA sequencing (KAS-seq) reveals dynamic and temporal changes in transcription in response to UVB exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 227.
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Patel, Chirayu, Jean-Pierre Gillet, Leif Stenke, Marita Lindberg, Magnus Bjorkholm, Jan Sjoberg, Kristina Viktorsson, Rolf Lewensohn, Ola Landgren, and Michael M. Gottesman. "Individualized Multidrug Resistance In Acute Myeloid Leukemia." Blood 116, no. 21 (November 19, 2010): 2491. http://dx.doi.org/10.1182/blood.v116.21.2491.2491.
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Abstract Abstract 2491 While much has been discovered in the laboratory regarding the mechanisms of multidrug resistance (MDR), based on phase III clinical trials of ATP-binding cassette (ABC) transporter modulators, these findings have not resulted in appreciable clinical benefit in acute myeloid leukemia (AML) patients. In this pilot study, we investigated the clinical relevance of 380 genes related to MDR in 31 samples from AML patients who had undergone conventional treatment, with 11 patients contributing samples at diagnosis and relapse, using TaqMan Low Density Arrays (TLDA). We and others have shown that the TaqMan-based qRT-PCR is superior to microarrays and SYBR-green-based qRT-PCR because of higher sensitivity and specificity in determining expression of highly homologous gene family members, such as the ABC transporters. 380 genes involved in metabolism, signal transduction, DNA repair, stress response, tumor suppressor activity, oncogenic transformation, apoptosis, and drug uptake or efflux were curated based on their potential role in MDR in the current literature. We found expression of four genes previously unreported in AML in both diagnostic and relapsed patient samples to correlate with duration of complete remission (CR) of induction chemotherapy: SLC7A8 and HSPE1 correlate negatively while GBP1 and ABCD2 correlate positively with CR duration (>2-fold change relative to the median, p<0.05). SLC7A8 is an L-type amino acid transporter that has not previously been found to be expressed in tumor cells, while GBP1 is a guanylate binding protein that might have antiproliferative and antiangiogenic effects. HSPE1 and ABCD2 are poorly characterized members of heat shock protein and ABC transporter families, respectively. NFKB1A, involved in the NFKB pathway, was found to correlate positively with CR duration in both samples at diagnosis and relapse (>2-fold change relative to the median, p<0.05). In a grouped comparison of all samples at relapse relative to diagnosis, GSTM5, a glutathione-S-transferase isoform involved in drug metabolism, was upregulated while TNF, tumor necrosis factor, was downregulated (>2 fold change compared to diagnosis, p<0.05). ABCB1, the best studied ABC transporter for which many modulators have been developed, was upregulated in some patients, while downregulated in others at relapse (>2 fold change compared to diagnosis, p<0.05). A patient-by-patient analysis of the paired samples revealed that each had a unique set of genes that was upregulated or downregulated at relapse relative to diagnosis, confirming the heterogeneity of AML with respect to acquired MDR. Finally, we assessed the ability of 15 cell lines to accurately depict MDR-linked gene expression in patients. The gene expression patterns of all cell lines were quite different from the patient samples, signifying the need to develop appropriate preclinical models for the study of MDR in AML. Disclosures: No relevant conflicts of interest to declare.
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McGrath, Lara, Ying Zheng, Simon Christ, Christian C. Sachs, Sihem Khelifa, Claudia Windmüller, Steve Sweet, et al. "Abstract 5737: Evaluation of the relationship between target expression and in vivo anti-tumor efficacy of AZD9592, an EGFR/c-MET targeted bispecific antibody drug conjugate." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5737. http://dx.doi.org/10.1158/1538-7445.am2023-5737.
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Abstract AZD9592 is a bispecific antibody drug conjugate (ADC) designed to deliver a topoisomerase 1 inhibitor (TOP1i) cytotoxic payload (AZ14170133) to tumor cells. AZD9592 selectively binds to epidermal growth factor receptor (EGFR) and c-MET, two cell surface receptors highly expressed in solid tumors including non-small-cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). Here we evaluate the pharmacodynamic activity of the TOP1i payload delivery by AZD9592 in an NSCLC-derived xenograft model using immunohistochemistry (IHC) approaches. Treatment-induced DNA double-strand breaks (DSB) and apoptotic cell death were measured using γH2AX, phospho-RAD-50 (pRAD50), and cleaved-caspase-3 (CC3) across increasing exposure to AZD9592. Furthermore, we report in vivo antitumor efficacy of AZD9592 in a panel of NSCLC and HNSCC patient-derived xenograft (PDX) models that were characterized for somatic tumor alterations, including oncogenic driver mutations in EGFR, tumor cell expression of EGFR and c-MET by IHC and deep-learning based image analysis, and targeted proteomics by mass spectrometry. Results demonstrate dose-dependent increases in pRAD50 and γH2AX upon treatment with AZD9592, signifying induction of DNA damage. Increased CC3 and reduced tumor volume (TV) in all treatment groups compared with control groups supports that AZD9592 induces tumor cell death due to formation of DNA DSB. In PDX experiments, tumor growth inhibition (TGI), defined as ≥30% reduction in TV from baseline after a single dose of AZD9592 8 mg/kg, was observed in 73% (16/22) of EGFR mutant NSCLC models. The models evaluated included tumors with or without prior exposure to EGFR tyrosine kinase inhibitors, and harboring diverse mutational profiles and heterogeneous expression levels of EGFR and c-MET. In EGFR wildtype NSCLC and HNSCC PDX, TGI was observed in 60% (12/20) and 44% (4/9) of models, respectively. IHC demonstrated an association of target expression and response to treatment, suggesting a potential predictive feature of response in tumors with elevated antigen expression. Targeted proteomics demonstrated an association between the expression of SLFN11, a known TOP1i sensitivity marker, and treatment response. Collectively, these results support the hypothesized mechanism of action of AZD9592: TOP1i induced tumor cell death due to formation of DNA DSB, and suggest opportunities in the treatment of tumors with a range of molecular features. AZD9592 is currently in a Phase 1 clinical trial in advanced solid malignancies. Citation Format: Lara McGrath, Ying Zheng, Simon Christ, Christian C. Sachs, Sihem Khelifa, Claudia Windmüller, Steve Sweet, Yeoun Jin Kim, Daniel Sutton, Michal Sulikowski, Arthur Lewis, Ivan Inigo, Nicolas Floch, Edward Rosfjord, Fernanda Arnaldez, Frank Comer. Evaluation of the relationship between target expression and in vivo anti-tumor efficacy of AZD9592, an EGFR/c-MET targeted bispecific antibody drug conjugate. [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 5737.
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Tawana, Kiran, Aline Renneville, Jun Wang, Panayiotis Georgiades, Xavier Thomas, Valerie Mialou, Aleksander Savic, et al. "Familial AML With Germline CEBPA Mutations: Extended Clinical Outcomes and Analysis Of Secondary Mutations Using Whole Exome Sequencing." Blood 122, no. 21 (November 15, 2013): 740. http://dx.doi.org/10.1182/blood.v122.21.740.740.
Full textAbstract:
Abstract Background Germline mutations in the N-terminal of CCAAT/enhancer binding protein α (CEBPA) are a feature of autosomal dominant AML. Despite the strong penetrance of these mutations, the age of disease onset varies considerably and is usually precipitated by acquiring a C-terminal mutation. Although biallelic CEBPA-mutations in sporadic AML are associated with favorable clinical outcomes, little is known about long-term survival or the secondary molecular events linked with familial cases. Aims We sought to establish the long term clinical outcomes in familial CEBPA-mutated AML and to examine the patterns of secondary mutations associated with leukemic transformation. Methods and Results Disease specific and follow up information was collected in 16 affected patients, from 7 pedigrees, published between 2004 and 2011. In 94% of patients (n=15), at least 3 years follow up was achieved. All pedigrees had a germline N-terminal CEBPA mutation and 17 of 18 documented disease episodes had an acquired C-terminal mutation. The age at AML diagnosis varied from 2-39 years (median 24.5 yrs) with a single asymptomatic carrier detected (now 23 yrs). With the exception of 1 patient diagnosed in 1963, all cases received combination chemotherapy at diagnosis. Additional consolidation comprised autologous stem cell transplantation (SCT, n=3) and allogeneic SCT in 1 patient failing to achieve CR post induction therapy. Ten patients had at least 1 further disease episode, the first recurrence presenting after a median of 2.1 years (range 0.5-14 yrs), 5 continued in CR and 1 patient was lost to follow up. In 3 out of 4 patients, where CEBPA was screened at recurrence, the acquired C-terminal mutations differed from diagnosis, signifying new episodes of AML. The median overall survival (OS) for the entire cohort was 20 years (1.1-46 yrs, n=16) and 17.3 years for patients with multiple disease episodes, reflecting durable responses to second line therapies. To identify potential co-operating mutations in CEBPA pedigrees, whole exome sequencing (WES) was performed in 7 tumor samples from 5 patients across 3 pedigrees, all with the germline mutation p.P23fs (Figure 1). All tumor DNA samples were sequenced with matched remission or skin DNA as a germline control. The number of acquired mutations in familial tumors was similar to sporadic disease, with 10-22 (median=14) non-synonymous tier 1 mutations per sample. In addition to the acquired C-terminal CEBPA mutation, these included established AML loci such as EZH2, TET2, WT1, GATA2, NRAS, CSF3R and the recently identified cohesin complex gene, SMC3. Of note, FLT3-ITD, NPM1 and DNMT3A mutations were absent in all tumors. A minimum of 2 established mutations were identified in each tumor and, at present, we can only speculate on which additional mutations are ‘driver' or ‘passenger' events. Reflecting findings in sporadic AML, biallelic CEBPA and GATA2 mutations co-occurred in both siblings from Pedigree 1 and were subsequently identified by Sanger sequencing in the child III.2 (Figure 1). All 3 patients continue in long term remission following chemotherapy. We were able to trace the clonal evolution in patient I.2 (Pedigree 3) by WES of 3 consecutive tumor samples which arose over a 17 year period. At diagnosis (Dx) the patient received induction and consolidation chemotherapy and remained disease free for 14 years. The second disease episode (R1) was treated with chemotherapy followed by autologous SCT and the third presentation (R2) was chemo-refractory. Tumor DNA from R2 was clonally related to Dx, sharing 7 identical mutations, including the original C-terminal CEBPA deletion. In contrast, R1 appeared molecularly distinct from Dx and R2, most likely representing a new clone which was subsequently eradicated with treatment. Conclusion This is the first report of long term clinical outcomes in familial CEBPA-mutated AML. Although many patients experienced disease recurrence, our extended follow up showed that OS remained favorable despite multiple episodes of disease. Assessment of C-terminal CEBPA mutations provided a unique insight into the recurrence of AML, with some patients appearing to develop completely new leukemic episodes. Although the penetrance of germline mutations is high, healthy carriers and late onset disease are noted, emphasizing the need for clinical vigilance and screening of all related potential SCT donors. Disclosures: No relevant conflicts of interest to declare.
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Casalaspi, David. "Sound and Fury Signifying Something: The Political Consequences of the Opt-Out Movement." Teachers College Record: The Voice of Scholarship in Education 123, no. 5 (May 2021): 1–26. http://dx.doi.org/10.1177/016146812112300508.
Full textAbstract:
Background and Context Grassroots activism is on the rise in American education, leading some scholars to announce the arrival of a “New Politics of Education” in which political elites and grassroots actors clash over foundational questions of policy and power. However, little research has examined just how consequential grassroots education activism might actually be in this new era. This study takes up this area of inquiry by examining the political consequences of the opt-out movement, arguably the largest and most high-profile grassroots education movement in recent history. Purpose The purpose of this study is to examine the political consequences of the opt-out movement in four New York school districts. Specifically, this study addresses the following research questions: What impact has the opt-out movement had on local education politics and policies, and do these effects vary across communities with different levels of opt-out activism? Research Design This study takes the form of a mixed methods, comparative case study analysis of the opt-out movement in four New York school districts purposefully sampled to exploit variation in district opt-out rates and racial demographics. Within each district, five sources of original data were collected, including a survey of Grade 3–8 parents, focus groups with opt-out parents and non-opt-out parents, interviews with district elites, interviews with key activists, and documentary sources. Data analysis was both quantitative (descriptive statistics) and qualitative (inductive simultaneous pattern coding). Findings Results suggest that while the opt-out movement has not yet produced many substantive changes in state or local test-based accountability policies, it has significantly increased and transformed parent engagement with education politics in the four case districts. These engagement effects were particularly pronounced in the high-opt-out districts. Conclusions and Recommendations This study concludes by offering a tempered view of the opt-out movement's impact on education policymaking while simultaneously indicating potentially significant changes in the way parents participate in education politics. In doing so, it produces implications for the study of education politics, policy, and activism more broadly. Principal among these are the importance for grassroots movements to build alliances with institutional actors in order to effect meaningful policy change, and the value of considering alternative definitions of movement “success” in future research on education politics and activism.
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Lamsal, Hiranya Lal. "The Russia–Ukraine Conflict: Nepal’s Foreign Policy in New Dimension of World Power." Unity Journal 4, no. 01 (February 15, 2023): 239–53. http://dx.doi.org/10.3126/unityj.v4i01.52244.
Full textAbstract:
How can Nepal engage with big powers? To do so, what kind of foreign policy should Nepal adopt? These questions are the main concerns of the study. In the present world scenario, foreign policy requires building a rapport with other countries Any country would need distinctive foreign policies to ensure national security, territorial integrity, and the protection of people’sovereignty. This study aims at exploring Nepal’s foreign policy in light of the ongoing Russia–Ukraine conflict. It follows an interpretative research design. It uses an inductive, qualitative method of study, collecting secondary data in the form of expert interviews, content-specific thematic analysis to construct a specific set of themes about the Russia-Ukraine conflict. The paper unfolds how foreign policy safeguards the territorial integrity of a country and protects the interest of its citizens, both within and outside the country. It has exemplified Ukraine’s situation as a reminder to small powers so that they tread a fine line in balancing between the preservation of sovereignty and signifying strategic empathy towards the interests of major powers.
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Buchok, Lianna. "V. Telychko’s “Children’s Album” as an example of the modern tonal image of the world: peculiarities of the musical vocabulary and melodic ideas." Problems of Interaction Between Arts, Pedagogy and the Theory and Practice of Education 49, no. 49 (September 15, 2018): 70–84. http://dx.doi.org/10.34064/khnum2-49.05.
Full textAbstract:
Background. The beginning of the development of musical art in Transcarpathia dates back to the end of the nineteenth century and lasts during the first third of the twentieth century. First of all, it was an interest in the genre of choral music (a synthetic genre based on the merging of the Word and Music), which fully corresponded to the enlightened spirit of life of the Transcarpathians under the political conditions of that time. And only in the second half of the twentieth century intensive blossoming of the varieties of instrumental (kind of «pure») music with its conceptually most complex types of creative thinking and adaptation to the methods of style transformation takes place. The piano music, one of the most abstract forms of the creative process, has revealed its peculiarities in this process. However, the researchers virtually never paid attention to piano pieces for children, which are naturally inferior by their practically necessary and didactically appropriate visual simplicity of musical vocabulary to the works of the so-called large genre. In addition, historically, the creative work of Transcarpathian composers has been considered only as a product of a purely regional significance. Therefore, it is important that the piano works of Transcarpathian composers for children should also be considered in the context of such integrity as the Intentional period of the music history, which has been defined as non-classical and at the same time permeated with the idea of global cultural synthesis Objectives. The essence of the tasks and the purpose is to present the "Child Album" by V. Telychko (the first in Transcarpathia sample of the genre of children’s musical album, 2016) as an example of the creation of the modern intonational image of the world - in its associative diversity and intentionality. Methods. A selection of research methods, namely, analytical (analysis and synthesis, induction and deduction, systematization, classification and generalization), comparative, systemic, phenomenological, functional, has been used in view of the holistic approach – in the spirit of spiritual development of the world. In this regard, the interpretive potential of the concepts of the intonational model and the modal nature of musical themes as types of thinking by sound images is considered methodologically appropriate: both purposefully focus attention of the recipient on the sound «body» and the intonational "soul" of the musical matter in the integrity of the creative idea of the work, and also is didactically productive in terms of comprehension of the architectonics of the world of music as a world of musical ideas. Results. V. Telichko’s "Children’s Album" is a cyclic structure of the linear/plot type, where step-by-step compositional and dramaturgical organization of the whole ensures the principle of successive naming of new, but equal in figurative semantic content pieces. At the same time, it will be superfluous to reflect on the fact that the structure of cycles such as "album" is rarely evaluated as such that it is actually "filled in" (for example, with memorable photos or pictures), and only since then its "white" (from alba) of the blank/empty sheets is filled in with the semantics and the logic of placement of fixed events, phenomena, impressions, etc in a certain order. Against the background of such reflection the memory recalls such "albums" of romantics: all of them are based on the logic of the course of a day lived by a child (for example, P. I. Tchaikovsky). V. Telichko’s principle of collecting pieces "into the album" has such a life-justifiable logic – the gradual flow of events of the day, embodied in a child’s only perception of the world and itself. The semantic code of the composer’s plan is referenced in his dedication: "I devote my love to grandchildren Angelina and Anna" - expressing love for grandchildren, admiring their fantasy and energy, caring for the formation of their worldview on a certain system of values (family, native land, diversity of traditions of the countries of the world , historical memory): the pieces "Morning", "My Mother", "Our Grandmother" represent an idea of an ingenuous and happy feeling of a child in the family; "Anna’s Teddy-Bear", "Angelina’s Hobbyhorse" and "Angelina’s Waltz " represent a lively imagination of children, each of them having a favorite game "theme"; the plays "About Transcarpathia", "Kolomyika", "Tropotyanka", "Long road" and "It’s raining" are outlined by the situation of instructive stories of grandfather about the regionally formed traditions of the Transcarpathians, their spirit and uneasy destiny; while the pieces "On Scotland", "On Slovakia" and "On Japan" outline the interests of somewhat different cognitive significance - the intention to comprehend a certain national "otherness", which has its own color of its culture; in the end, "A Lullaby for Anna" creates, so to say, a backlash against the grand finale-prologue, consisting of the pieces "On Austria" (the cultural center of the European musical classicism) and "On Romania" (regionally closest to Transcarpathia country). Another signifying circumstance of the idea and plan of the cycle refers to the types of performances and personification of images, both as members of the family circle and as a certain social unity: in addition to the versions of solo performance, in a considerable number of plays there is ensemble performance in four and six hands; at the same time, each of the parts is composed as a certain texture layer, which in aggregate (duo, terzetto) gives the effect of an "orchestral" score. However, the most important thing is that for the instrumentalist performer, and for the listener or analyst (who is also a "listener"), the "Children’s Album" by V. Telichko is a test of the ability to perceive musical vocabulary in the form of a certain sound form/idea with which it is necessary to have a relationship according to the algorithm of personal identification. On the one hand, in the musical text there is an opportunity to recognize the classical models of musical vocabulary (cantilena, recitation, motility, general forms of motion, signaling, sound illustration); and on the other - due to the constructive interference of the classical techniques of the creation of musical matter (emancipated dissonance, the non-systemic character of the tonality, etc.) the meanings are accumulated. Another important component of the composer’s plan is to introduce a purely methodical (level of methodical reception) task of developing the technology of the game on the piano into the original sound form/idea, which first of all requires a skillful usage of all the fingers. Conclusions. As a research material the "Children’s Album" by a contemporary composer from Transcarpathia, V. Telichko provides several important and mutually perceptible scientific tasks directly related to musicology and pedagogical practice: testing of the theoretically updated analytical apparatus for tracking the intonational field of music and its thoughts and comprehension of the didactically expedient implementation of its results in the educational sphere; in particular, in terms of the prospective guideline for the development of musicality (a high measure of the ability to self-identification with the musical image) and the piano skills of a child musician.
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Buchok, Lianna. "V. Telychko’s “Children’s Album” as an example of the modern tonal image of the world: peculiarities of the musical vocabulary and melodic ideas." Problems of Interaction Between Arts, Pedagogy and the Theory and Practice of Education 49, no. 49 (September 15, 2018): 70–84. http://dx.doi.org/10.34064/khnum1-49.05.
Full textAbstract:
Background. The beginning of the development of musical art in Transcarpathia dates back to the end of the nineteenth century and lasts during the first third of the twentieth century. First of all, it was an interest in the genre of choral music (a synthetic genre based on the merging of the Word and Music), which fully corresponded to the enlightened spirit of life of the Transcarpathians under the political conditions of that time. And only in the second half of the twentieth century intensive blossoming of the varieties of instrumental (kind of «pure») music with its conceptually most complex types of creative thinking and adaptation to the methods of style transformation takes place. The piano music, one of the most abstract forms of the creative process, has revealed its peculiarities in this process. However, the researchers virtually never paid attention to piano pieces for children, which are naturally inferior by their practically necessary and didactically appropriate visual simplicity of musical vocabulary to the works of the so-called large genre. In addition, historically, the creative work of Transcarpathian composers has been considered only as a product of a purely regional significance. Therefore, it is important that the piano works of Transcarpathian composers for children should also be considered in the context of such integrity as the Intentional period of the music history, which has been defined as non-classical and at the same time permeated with the idea of global cultural synthesis Objectives. The essence of the tasks and the purpose is to present the "Child Album" by V. Telychko (the first in Transcarpathia sample of the genre of children’s musical album, 2016) as an example of the creation of the modern intonational image of the world - in its associative diversity and intentionality. Methods. A selection of research methods, namely, analytical (analysis and synthesis, induction and deduction, systematization, classification and generalization), comparative, systemic, phenomenological, functional, has been used in view of the holistic approach – in the spirit of spiritual development of the world. In this regard, the interpretive potential of the concepts of the intonational model and the modal nature of musical themes as types of thinking by sound images is considered methodologically appropriate: both purposefully focus attention of the recipient on the sound «body» and the intonational "soul" of the musical matter in the integrity of the creative idea of the work, and also is didactically productive in terms of comprehension of the architectonics of the world of music as a world of musical ideas. Results. V. Telichko’s "Children’s Album" is a cyclic structure of the linear/plot type, where step-by-step compositional and dramaturgical organization of the whole ensures the principle of successive naming of new, but equal in figurative semantic content pieces. At the same time, it will be superfluous to reflect on the fact that the structure of cycles such as "album" is rarely evaluated as such that it is actually "filled in" (for example, with memorable photos or pictures), and only since then its "white" (from alba) of the blank/empty sheets is filled in with the semantics and the logic of placement of fixed events, phenomena, impressions, etc in a certain order. Against the background of such reflection the memory recalls such "albums" of romantics: all of them are based on the logic of the course of a day lived by a child (for example, P. I. Tchaikovsky). V. Telichko’s principle of collecting pieces "into the album" has such a life-justifiable logic – the gradual flow of events of the day, embodied in a child’s only perception of the world and itself. The semantic code of the composer’s plan is referenced in his dedication: "I devote my love to grandchildren Angelina and Anna" - expressing love for grandchildren, admiring their fantasy and energy, caring for the formation of their worldview on a certain system of values (family, native land, diversity of traditions of the countries of the world , historical memory): the pieces "Morning", "My Mother", "Our Grandmother" represent an idea of an ingenuous and happy feeling of a child in the family; "Anna’s Teddy-Bear", "Angelina’s Hobbyhorse" and "Angelina’s Waltz " represent a lively imagination of children, each of them having a favorite game "theme"; the plays "About Transcarpathia", "Kolomyika", "Tropotyanka", "Long road" and "It’s raining" are outlined by the situation of instructive stories of grandfather about the regionally formed traditions of the Transcarpathians, their spirit and uneasy destiny; while the pieces "On Scotland", "On Slovakia" and "On Japan" outline the interests of somewhat different cognitive significance - the intention to comprehend a certain national "otherness", which has its own color of its culture; in the end, "A Lullaby for Anna" creates, so to say, a backlash against the grand finale-prologue, consisting of the pieces "On Austria" (the cultural center of the European musical classicism) and "On Romania" (regionally closest to Transcarpathia country). Another signifying circumstance of the idea and plan of the cycle refers to the types of performances and personification of images, both as members of the family circle and as a certain social unity: in addition to the versions of solo performance, in a considerable number of plays there is ensemble performance in four and six hands; at the same time, each of the parts is composed as a certain texture layer, which in aggregate (duo, terzetto) gives the effect of an "orchestral" score. However, the most important thing is that for the instrumentalist performer, and for the listener or analyst (who is also a "listener"), the "Children’s Album" by V. Telichko is a test of the ability to perceive musical vocabulary in the form of a certain sound form/idea with which it is necessary to have a relationship according to the algorithm of personal identification. On the one hand, in the musical text there is an opportunity to recognize the classical models of musical vocabulary (cantilena, recitation, motility, general forms of motion, signaling, sound illustration); and on the other - due to the constructive interference of the classical techniques of the creation of musical matter (emancipated dissonance, the non-systemic character of the tonality, etc.) the meanings are accumulated. Another important component of the composer’s plan is to introduce a purely methodical (level of methodical reception) task of developing the technology of the game on the piano into the original sound form/idea, which first of all requires a skillful usage of all the fingers. Conclusions. As a research material the "Children’s Album" by a contemporary composer from Transcarpathia, V. Telichko provides several important and mutually perceptible scientific tasks directly related to musicology and pedagogical practice: testing of the theoretically updated analytical apparatus for tracking the intonational field of music and its thoughts and comprehension of the didactically expedient implementation of its results in the educational sphere; in particular, in terms of the prospective guideline for the development of musicality (a high measure of the ability to self-identification with the musical image) and the piano skills of a child musician.
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Biswas, Srijit, Anindita Sengupta, Dipankar Kakati, and Rahul Banerjee. "The transition from conventional biodiesel combustion to RCCI with CNG/ethanol induction in CI engine: A comparative combustion analysis and relative effects on performance-emissions." International Journal of Engine Research, September 28, 2022, 146808742211236. http://dx.doi.org/10.1177/14680874221123615.
Full textAbstract:
Concerning the national biofuel policies in India, increasing plant-based fuels and lowering the use of fossil diesel in CI engines reduces the burden on foreign exchange and carbon footprints in the environment, which helps achieve “net-zero carbons emissions.” In this present study, Mahua biodiesel (BD) was used here as an ignition energy source, and CNG/ethanol (Et) was used here as the primary energy source replacing the biodiesel with a significant energy share during the combustion process. The effects of various injection and reactivity phasing strategies on a diesel engine’s combustion characteristics has been evaluated here. However, effect of this combustion characteristics on the corresponding performance and emission has also been evaluated here. This study revealed the ignition delay (ID) and combustion duration (CD) trade-off for almost every combustion phase achieved here during the testing. This analysis also incorporates the widespread effect of combustion characteristics on the performance and emission behavior of the diesel engine for both types of fuel combinations, that is, CNG + BD and Et + BD operation. For example, the lowest ID for CNG enriched combustion was 26.62% greater than ethanol enriched combustion, signifying that the ethanol delayed the start of ignition at polit-main angle of 35°-05° CA. Hence, NHC, PM, and CO2 emissions registered a lower footprint for CNG-BD operation, while ethanol-BD mode reported lower CO emission. However, ethanol-enriched combustion registered a 31.25% higher maximum CD than CNG-coupled operation, signifying a more extended period of energy release. CNG-BD operation also observed lower NHC, CO, and CO2 footprint corresponding to maximum combustion duration, and ethanol-BD mode reported lower PM emission.
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White, Brian S., Suleiman A. Khan, Mike J. Mason, Muhammad Ammad-ud-din, Swapnil Potdar, Disha Malani, Heikki Kuusanmäki, et al. "Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia." npj Precision Oncology 5, no. 1 (July 23, 2021). http://dx.doi.org/10.1038/s41698-021-00209-9.
Full textAbstract:
AbstractThe FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vivo drug response of primary patient samples. We find that ex vivo samples often exhibit a general sensitivity to (any) drug exposure, independent of drug target. We observe that this “general response across drugs” (GRD) is associated with FLT3-ITD mutations, clinical response to standard induction chemotherapy, and overall survival. Further, incorporating GRD into expression-based regression models trained on one of the studies improved their performance in predicting ex vivo response in the second study, thus signifying its relevance to precision oncology efforts. We find that venetoclax response is independent of GRD but instead show that it is linked to expression of monocyte-associated genes by developing and applying a multi-source Bayesian regression approach. The method shares information across studies to robustly identify biomarkers of drug response and is broadly applicable in integrative analyses.