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O’Brien, Anne Therese. "Ethical Acknowledgment of Soil Ecosystem Integrity amid Agricultural Production in Australia." Environmental Humanities 12, no. 1 (2020): 267–84. http://dx.doi.org/10.1215/22011919-8142341.
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Abstract The growing adoption of no-till cropping and other minimal-impact farming practices in recent decades signals a shift in how soil is understood and valued. Eschewing vigorous disturbance, standard in the West (and beyond) since the Neolithic Revolution, farmers instead learn to intervene with the soil profile more sensitively. This article focuses on the concept of soil integrity and its significance for farmers’ ethical relationship to soils in everyday practice, using the case study of pasture cropping, an Australian form of agriculture that extends no-till methods to embrace ecological relationships within and beyond the soil. Prioritizing the integrity of soil ecosystems often requires reconceiving what soil is and should be. Soil can be difficult to see as ethically significant partly because it often appears as a granular bulk good, seemingly featureless and fungible. To counteract this, farmers who care for soil integrity use various heuristic and aesthetic strategies to render soil integrity more perceptible and intelligible. The author considers how a keener perception of soil integrity may enable greater attunement toward the soil condition, acknowledgement of soil distress, and thus ethical responsiveness. The article considers this through a broader discussion of phenomenological ethics.
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Böttger, A., and B. A. Spruce. "Proenkephalin is a nuclear protein responsive to growth arrest and differentiation signals." Journal of Cell Biology 130, no. 6 (1995): 1251–62. http://dx.doi.org/10.1083/jcb.130.6.1251.
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Neuropeptide precursors are traditionally viewed as molecules destined to be cleaved into bioactive peptides, which are then released from the cell to act on target cell surface receptors. In this report we demonstrate nuclear localization of the enkephalin precursor, proenkephalin, in rodent and human embryonic fibroblasts (Swiss 3T3 and MRC-5 cells) and in rodent myoblasts (C2C12 cells). Nuclear proenkephalin, detected by immunofluorescence with a panel of antiproenkephalin monoclonal antibodies, is distributed predominantly in three patterns. Selective abolition of these patterns with salt, nuclease, or methanol is associated with liberation of immunoprecipitable proenkephalin into the extraction supernatant. Proenkephalin antigenic domains, mapped using phage display libraries and synthetic peptides, are differentially revealed in the three distribution patterns. Selective epitope revelation may reflect different conformational forms of proenkephalin or its existence in complexes with other nuclear proteins, forms which therefore have different biochemical associations with the nuclear substructure. In fibroblast cell populations in transition to growth arrest, nuclear proenkephalin responds promptly to mitogen withdrawal and cell-cell contact by transient, virtually synchronous unmasking of multiple antigenic domains in a fine punctate distribution. A similar phenomenon is observed in myoblasts undergoing differentiation. The acknowledgment of growth arrest and differentiation signals by nuclear proenkephalin suggests its integration with transduction pathways mediating these signals. To begin to address the mechanism of nuclear targeting, we have transfected mutated and nonmutated proenkephalin into COS (African green monkey kidney) cells. Nonmutated proenkephalin is localized exclusively in the cytoplasm; however, proenkephalin mutated at the first ATG codon, or devoid of its signal peptide sequence, is targeted to the nucleus as well as to the cytoplasm. From this we speculate that nuclear proenkephalin arises from a primary translation product that lacks a signal peptide sequence because of initiation at a different site.
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Dieudonné, Yoann, Shlomi Dolev, Franck Petit, and Michael Segal. "Explicit Communication Among Stigmergic Robots." International Journal of Foundations of Computer Science 30, no. 02 (2019): 315–32. http://dx.doi.org/10.1142/s0129054119500072.
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In this paper, we investigate avenues for the exchange of information (explicit communication) among deaf and mute mobile robots scattered in the plane. We introduce the use of movement-signals (analogously to flight signals and bees waggle) as a mean to transfer messages, enabling the use of distributed algorithms among robots. We propose one-to-one deterministic movement protocols that implement explicit communication among semi-synchronous robots. We first show how the movements of robots can provide implicit acknowledgment in semi-synchronous systems. We use this result to design one-to-one communication among a pair of robots. Then, we propose two one-to-one communication protocols for any system of [Formula: see text] robots. The former works for robots equipped with observable IDs that agree on a common direction (sense of direction). The latter enables one-to-one communication assuming robots devoid of any observable IDs or sense of direction. All protocols (for either two or any number of robots) assume that no robot remains inactive forever. However, they cannot avoid that the robots move either away or closer to each others, by the way requiring robots with an infinite visibility. In this paper, we also present how to overcome these two disadvantages (some activity of every robot and infinite visibility). Our protocols enable the use of distributing algorithms based on message exchanges among swarms of stigmergic robots. They also allow robots to be equipped with the means of communication to tolerate faults in their communication devices.
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Zhang, Weina, Zhongjian Chen, Yichen Kang, et al. "Genome-wide analysis of lectin receptor-like kinases family from potato (Solanum tuberosum L.)." PeerJ 8 (June 10, 2020): e9310. http://dx.doi.org/10.7717/peerj.9310.
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Lectin receptor-like kinases (LecRLKs) are involved in responses to diverse environmental stresses and pathogenic microbes. A comprehensive acknowledgment of the family members in potato (Solanum tuberosum) genome is largely limited until now. In total, 113 potato LecRLKs (StLecRLKs) were first identified, including 85 G-type, 26 L-type and 2 C-type members. Based on phylogenetic analysis, StLecRLKs were sub-grouped into seven clades, including C-type, L-type, G-I, G-II, G-III G-IV and G-V. Chromosomal distribution and gene duplication analysis revealed the expansion of StLecRLKs occurred majorly through tandem duplication although the whole-genome duplication (WGD)/segmental duplication events were found. Cis-elements in the StLecRLKs promoter region responded mainly to signals of defense and stress, phytohormone, biotic or abiotic stress. Moreover, expressional investigations indicated that the family members of the clades L-type, G-I, G-IV and G-V were responsive to both bacterial and fungal infection. Based on qRT-PCR analysis, the expressions of PGSC0003DMP400055136 and PGSC0003DMP400067047 were strongly induced in all treatments by both Fusarium sulphureum (Fs) and Phytophthora infestans (Pi) inoculation. The present study provides valuable information for LecRLKs gene family in potato genome, and establishes a foundation for further research into the functional analysis.
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Rudert, Selma C., Andrew H. Hales, Rainer Greifeneder, and Kipling D. Williams. "When Silence Is Not Golden: Why Acknowledgment Matters Even When Being Excluded." Personality and Social Psychology Bulletin 43, no. 5 (2017): 678–92. http://dx.doi.org/10.1177/0146167217695554.
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Following ostracism, individuals are highly sensitive to social cues. Here we investigate whether and when minimal acknowledgment can improve need satisfaction following an ostracism experience. In four studies, participants were either ostracized during Cyberball (Studies 1 and 2) or through a novel apartment-application paradigm (Studies 3 and 4). To signal acknowledgment following ostracism, participants were either thrown a ball a few times at the end of the Cyberball game, or received a message that was either friendly, neutral, or hostile in the apartment-application paradigm. Both forms of acknowledgment increased need satisfaction, even when the acknowledgment was hostile (Study 4), emphasizing the beneficial effect of any kind of acknowledgment following ostracism. Reinclusion buffered threat immediately, whereas acknowledgment without reinclusion primarily aided recovery. Our results suggest that minimal acknowledgment such as a few ball throws or even an unfriendly message can reduce the sting of ostracism.
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Hendrickson, Wayne A. "Transduction of biochemical signals across cell membranes." Quarterly Reviews of Biophysics 38, no. 4 (2005): 321–30. http://dx.doi.org/10.1017/s0033583506004136.
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1. Introduction 3212. Tyrosine kinase receptors 3223. Histidine kinase sensors 3254. G-protein coupled receptors 3275. Principles 3286. Acknowledgments 3297. References 330Biological cells need to be responsive to various stimuli, primarily chemical ligands from their environments. Specific receptor molecules embedded in the plasma membrane detect the different biochemical signals that impact the cell, and these receptors are the conduits for transmission of this information to the cell interior for action. There are several classes of signal transduction receptors and many specific receptors within each of the major classes. This review emphasizes the structural biology of three major classes of transmembrane receptors – tyrosine kinase receptors, histidine kinase sensors, and G-protein coupled receptors. Biophysical principles that govern the processes of signal transduction across cell membranes are also discussed.
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Sophia Jasmine, G., D. Magdalin Mary, and A. Sheela. "Penmanship and signal acknowledgment utilizing inertial pen." Materials Today: Proceedings 45 (2021): 8110–14. http://dx.doi.org/10.1016/j.matpr.2021.01.677.
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Kunt, Murat. "Acknowledgment." Signal Processing 21, no. 4 (1990): 351–54. http://dx.doi.org/10.1016/0165-1684(90)90105-8.
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Kunt, Murat. "Acknowledgment." Signal Processing 25, no. 3 (1991): 391–94. http://dx.doi.org/10.1016/0165-1684(91)90123-z.
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Kunt, Murat. "Acknowledgment." Signal Processing 40, no. 2-3 (1994): 343–51. http://dx.doi.org/10.1016/0165-1684(94)90082-5.
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Noronha, Thiago R., Miguel Mitne-Neto, and Maria L. Chauffaille. "Additional Information Offered By Snpa in Myelodysplastic Syndromes with Excess Blasts (MDS-EB) and Future Perspectives." Blood 128, no. 22 (2016): 5552. http://dx.doi.org/10.1182/blood.v128.22.5552.5552.
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Abstract Introduction: The detection of chromosomal abnormalities in myelodysplastic syndromes (MDS) supports the diagnosis, classification, prognostic stratification, therapy option, treatment monitoring and better understanding of the biology of disease. The main chromosomal abnormalities of MDS are losses and gains of genetic material, and these changes are among the most important prognostic parameters in IPSS-R. As a consequence, major advances have been achieved in the treatment and survival of patients. However, nearly half of the patients present a normal karyotype, which prevents their further characterization. Therefore, there is the desire to increase the abnormalities detection rate by other methods. Single nucleotide polymorphisms array (SNPa), also referred to as chromosomal microarray, is a sensitive technology used to perform high-resolution genome-wide DNA losses, gains and copy-neutral loss of heterozygosity (CN-LOH). The genomic DNA is hybridized to polymorphic probes which are SNP markers and non-polymorphic probes which are copy number markers, providing information about CN-LOH and copy number alteration (CNA), respectively. Previous studies have shown that the addition of the SNPa to karyotype (KT) increases by 28% the detection rate of cytogenetic abnormalities. Objective: To substantiate this idea we describe two cases of MDS to whom SNPa added valued information to karyotype. Methods: DNA was extracted from bone marrow cells for genomic clonal evaluation. The DNA was digested, amplified, fragmented, labeled and hybridized to the chip (Affymetrix - CytoScan HD®) containing the probes. The chip was scanned to detect the signals' intensity emitted by the hybridized probes which were further analyzed by a software (ChAS) that allows visualization of CNA and CN-LOH. CNA´s analysis relies on the comparison of the obtained signals to a reference diploid DNA signal, and the difference encountered is characterized as loss or gain. CN-LOH analysis is based on two possible nucleotide signals (A or B), which are evaluated to discriminate three genotypes: AA, AB and BB. CN-LOH occurs when one allele is lost and duplicate another, resulting in genotypes AA or BB. Results: Case 1, 64y-male-patient, classified as MDS-EB (WHO 2016), Bone marrow histology showed grade II fibrosis. KT: 46,XY,del(5)(q15q33),del(17)(p11.2)[16] / 46,XY[4]. SNPa: 3p21.31p21.2 CN-LOH; 5q21.1q35.3 loss (CN:1.00); -7; +8; 12p13.33p12.3, 12p12.1p11.22, 12q22q23.3 loss (CN:1.00); -16; 17p13.3p11.2 mosaic loss (CN: 1.50) and -Y. Case 2, 74y-male-patient, classified as MDS-EB (WHO 2016), Bone marrow histology showed grade II/lll fibrosis. KT: 46,XY[15]. SNPa: 21q21.1q22.3 CN-LOH. Discussion and Conclusion: The SNPa has the advantage of detecting genomic alterations regardless of the cell cycle, even when the cell is quiescent or growth is defective. It also enables the identification of CN-LOH (also known as uniparental disomy, UPD), submicroscopic amplifications and deletions that are not detected by KT. On the other hand, SNPa does not allow the identification of balanced translocations and polyploidy. In case 1, after SNPa analysis, some chromosomal abnormalities (−7, +8, −16 and −Y) were found in sporadic metaphases during the KT reanalysis, but had not initially been described because they did not meet the criterion to be considered as a cytogenetic clone. The risk-stratification (IPSS-R) for this patient was intermediate, but the addition of the SNPa results the risk-stratification could be changed to very poor. Seven months after diagnosis the patient developed acute myeloid leukemia and died. In case 2, CN-LOH detected by SNPa could be responsible for homozygosity of mutations in critical genes located in the 21p region, such as RUNX1 that encodes a protein, which is a transcription factor critical in hematopoiesis. Indeed, sequencing of candidate genes in CN-LOH regions should be considered a priority in the search of driver mutations of MDS. Twenty-four months after diagnosis the patient died due to other non-hematologic causes. In Summary, SNPa analysis may add value to KT non-informative results and occasionally reveal cryptic abnormalities not recognized by karyotyping. However, SNPa analysis should be viewed as a complimentary tool. Acknowledgment: The SNPa test was supported by Grupo Fleury Disclosures No relevant conflicts of interest to declare.
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Ali, Mohammed Hasan, and Qasim Mohamed Al Azze. "Design and implementation a security system for bank using voice recognition." International Journal of Power Electronics and Drive Systems (IJPEDS) 10, no. 4 (2019): 2126. http://dx.doi.org/10.11591/ijpeds.v10.i4.pp2126-2129.
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In this work, a new security system design is demonstrated based on the sound signal for bank protection. Voice Acknowledgment Module is placed on the gate of the safe. Voice Acknowledgment Module is set to perceive the capable client as indicated by his sound recurrence reaction. The plan could program to permit tow clients for greater adaptability the card location strategy is executed utilizing individual data information to permit other client in the framework. A delicate camera is accustomed to observing the developments in the structure and for the reasons for wellbeing and security. All these sensors are controlled by arduino.<strong> </strong>
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Ding, Wei, Tait D. Shanafelt, Clive S. Zent, et al. "The AKT Inhibitor MK2206 In Combination With Rituximab and Bendamustine Is Tolerable and Active In Relapsed Or Refractory Chronic Lymphocytic Leukemia: Results From a Phase 1 Study (NCCTG N1087 Alliance)." Blood 122, no. 21 (2013): 2882. http://dx.doi.org/10.1182/blood.v122.21.2882.2882.
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Abstract Backgrounds B cell receptor (BCR) signals and microenvironment protection have been recognized to have key influences on CLL survival and activation. Akt activation is down-stream of the BCR signaling cascade and is critical in the mediation of the bi-directional interactions between CLL B-cells and bone marrow stroma. MK2206 is an allosteric Akt inhibitor previously tested for safety in solid tumor patients. Our preclinical data has demonstrated the synergy of MK2206 with bendamustine (B) to induce CLL apoptosis in vitro. MK2206 also abolished the signal activation and cytokine production induced by BCR ligation in CLL leukemic cells (Ding, ASH 2012). Therefore, we conducted a phase 1 trial testing the safety and efficacy of MK2206 in combination with bendamustine and rituximab (BR) for patients with relapsed/refractory CLL. Methods A phase 1 dose-escalation study was designed to define the maximum tolerated dose (MTD) as well as the safety and efficacy of 3 dose levels (90 mg or 135 mg or 200 mg weekly) of the oral Akt inhibitor MK2206 in combination with bendamustine (70 mg/m2 daily for 2 days in each cycle) and rituximab (cycle 1: 375 mg/m2, cycle 2-6: 500 mg/m2) therapy in relapse/refractory CLL patients. To test the targeting efficacy of MK2206 on Akt and downstream signals, we designed a one-week “run-in” of single agent MK2206 before the initiation of BR during cycle 1. MK2206 was then given along with BR on day 1 of cycles 2-6. Tumor response was evaluated 2 months after the 6th/last cycle of therapy based on IWCLL 2008 criteria. Correlative laboratory studies included assessment of Akt signaling and the plasma cytokine levels (multiplex beads assay (Invitrogen)) at baseline and after one week of first dose of single agent MK2206. Results Nine patients (median age 68) were enrolled in the phase I portion of this trial. All 9 patients had unmutated immunoglobulin heavy chain variable region genes (IGHV) and 4 had del(11q). Six had received prior chemoimmunotherapy (CIT: FCR or PCR or PCO) and 5 had high risk disease defined as early progression within 26 months of the last CIT. Three had received alemtuzumab containing regimen. We have observed potent lymphocyte mobilization in all evaluated patients (n=7) after one-dose of MK2206 during week 1 (mean increase ALC: 35%) as well as reductions of plasma CCL3, CCL4 and CCL2 in the majority of the patients. A single dose-limiting toxicity (DLT) (febrile neutropenia and hemolytic anemia) was observed at dose level 1 (90 mg weekly) among 6 patients treated at this dose. Two patients with dose-limiting toxicities at dose level 2 (135 mg weekly) were observed where one patient had a rash and one patient had dehydration and febrile neutropenia among three patients treated at this dose. Accordingly, the 90 mg once weekly dose was determined to be the MTD for phase 2 trial testing. The most frequent grade 3 or 4 adverse events observed to date were neutropenia (44%) including febrile neutropenia (22%), rash (22%), diarrhea (22%), nausea and vomiting (11%), dehydration (11%), hemolytic anemia (11%) and thrombocytopenia (11%). The frequency of cytopenias was similar to the published German experience with BR (50% grade 3 or 4 hematological toxicities compared to 44% in N1087) in relapsed CLL patients (Fischer, JCO 2011). The median number of cycles received was 6 (range 1-6). Using an intent to treat analysis, two patients achieved complete response (CR, n= 2, 22%), one patient achieved nodular partial response (nPR, n=1, 11%) and five patients achieved a partial response (PR, n=5, 56%). The overall response rate (ORR) is 89%. Conclusion The Akt inhibitor MK2206 in combination with BR is well tolerated in patients with relapsed/refractory CLL. Single dose of MK2206 inhibits Akt phosphorylation, mobilizes leukemic cells and decreases plasma cytokines involved in BCR signals. The preliminary efficacy of this combination demonstrated promising results with a 89% ORR and 22% CR albeit in the small phase 1 cohort. These results compare favorably to BR alone (9% CR and 59% ORR) in relapsed/refractory CLL patients. Phase 2 testing of this combination is now underway. Acknowledgment This work was supported by the funding from NCI grant K23CA160345 (WD), NCI grant CA95241 (NEK) and Alliance for Clinical Trials in Oncology (CA025224 and CA33601). Disclosures: Off Label Use: MK2206, used in a phase 1 trial of relapsed CLL disease. Shanafelt:Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Zent:Novartis: Research Funding; GlaxSmithKline: Research Funding; Biothera: Research Funding; Genzyme: Research Funding; Genentech : Research Funding. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.
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Malhotra, Neha, and Geeta Rani. "Plant’s Leaf Analysis Using Pattern Recognition Algorithm." Journal of Computational and Theoretical Nanoscience 17, no. 11 (2020): 5167–73. http://dx.doi.org/10.1166/jctn.2020.9359.
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Plant species identification is an important area of research which is required in number of regions. Design and development of an automatic leaf based plant species identification system is a challenging task. The initial step of any coordinating/acknowledgment framework is to identify intrigue areas in the pictures and portray them. The proposed system is based on pre-processing, feature extraction and their weighted normalization and finally classification. In this paper, pattern recognition/retrieval techniques are studied by extraction of novel features in all three domains and their performance has been evaluated based on Entropy, Peak-Signal-to-Noise-Ratio (PSNR), Standard Deviation (SD), Euler Number and Gradient Magnitude Similarity Deviation. This paper presents scientific ideas for distinguishing and depicting image features.
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Statkus, Arūnas, Šarūnas Paulikas, and Audrius Krukonis. "TCP Acknowledgment Optimization in Low Power and Embedded Devices." Electronics 10, no. 6 (2021): 639. http://dx.doi.org/10.3390/electronics10060639.
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Paper investigates transport control protocol (TCP) acknowledgment (ACK) optimization in low power or embedded devices to improve their performance on high-speed links by limiting the ACK rate. Today the dominant protocol for interconnecting network devices is the TCP and it has a great influence on the entire network operation if the processing power of network devices is exhausted to the processing data from the TCP stack. Therefore, on high-speed not congested networks the bottleneck is no longer the network link but low-processing power network devices. A new ACK optimization algorithm has been developed and implemented in the Linux kernel. Proposed TCP stack modification minimizes the unneeded technical expenditure from TCP flow by reducing the number of ACKs. The results of performed experiments show that TCP ACK rate limiting leads to the noticeable decrease of CPU utilization on low power devices and an increase of TCP session throughput but does not impact other TCP QoS parameters, such as session stability, flow control, connection management, congestion control or compromises link security. Therefore, more resources of the low-power network devices could be allocated for high-speed data transfer.
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Chaudhuri, M., and M. Heinrich. "The impact of negative acknowledgments in shared memory scientific applications." IEEE Transactions on Parallel and Distributed Systems 15, no. 2 (2004): 134–50. http://dx.doi.org/10.1109/tpds.2004.1264797.
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Lin, Hong, Mei Liu, Huaicheng Yan, Jinliang Liu, and Shan Lu. "Approximate solution to optimal linear quadratic Gaussian control over non-acknowledgment networks." Journal of the Franklin Institute 357, no. 4 (2020): 2049–66. http://dx.doi.org/10.1016/j.jfranklin.2019.11.046.
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Skarakis-Doyle, Elizabeth, Nancy MacLellan, and Kathleen Mullin. "Nonverbal Indicants of Comprehension Monitoring in Language-Disordered Children." Journal of Speech and Hearing Disorders 55, no. 3 (1990): 461–67. http://dx.doi.org/10.1044/jshd.5503.461.
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This study investigated normal and language-disordered (LD) children's patterns of nonverbal behavior in response to messages varying in degree of ambiguity. Each LD child was matched to two normally developing children: one for comprehension level (LM) and the other for chronological age (CM). All children participated in a videotaped ambiguity detection task. Nonverbal behaviors that were produced between the time the message was completed and the examiner's acknowledgment of the response were scored for type of behavior exhibited including eye contact, hand behavior, body movement, and smile. Results demonstrated that all subjects increased their nonverbal behavior (e.g., eye contact) from unambiguous to ambiguous message conditions, suggesting awareness of the differences in these message types at a rudimentary level. Most often nonverbal indication was the only signal of ambiguity detection exhibited by the LD children and their LM peers. Only the CM children concurrently indicated awareness through more direct means (i.e., verbalization and pointing to all possible referents) in a consistent and accurate manner. The finding that LD children did differentiate inadequate from adequate messages in a rudimentary manner suggests that clinicians might promote the intentionality of these preintentional nonverbal behaviors as a possible intervention strategy.
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Ibrahim, Muhammad K., Mahmoud H. Ismail, and M. Watheq El-Kharashi. "Novel Distributed Scheduling Algorithms for mmWave Mesh Networks." Journal of Circuits, Systems and Computers 27, no. 08 (2018): 1850118. http://dx.doi.org/10.1142/s0218126618501189.
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This paper addresses throughput improvement in millimeter-wave (mmWave) mesh networks via two novel distributed scheduling algorithms. The first one uses packet aggregation and block acknowledgment (ACK) that were introduced in the IEEE Std 802.11e-2005 for WiFi. Specifically, a distributed time-division multiplexing scheduling algorithm, which targets increasing the network capacity via reserving as many contiguous slots as possible for each node, is proposed thus enabling packet aggregation. This algorithm achieves its goal when the operating signal-to-noise ratio (SNR) is significantly high. If that is not the case, the second proposed algorithm can be used. It is a distributed one that starts initially with a random feasible schedule determined cooperatively between nodes. The algorithm then tries to reach better feasible schedules via parallel and successive local searches without violating feasibility constraints. Extensive simulations show that the first algorithm improves the network throughput by almost [Formula: see text] compared to the well-known memory-guided directional medium access control (MDMAC) due to reducing the transmission overhead. The second proposed algorithm is shown to increase the number of reserved slots by about [Formula: see text] over MDMAC. Both algorithms are shown to either increase or almost maintain the same degree of fairness among the nodes as quantified by Jain’s fairness index.
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Park, Chester Sungchung, and Sungkyung Park. "Implementation of a Fast Link Rate Adaptation Algorithm for WLAN Systems." Electronics 10, no. 1 (2021): 91. http://dx.doi.org/10.3390/electronics10010091.
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With a target to maximize the throughput, a fast link rate adaptation algorithm for IEEE 802.11a/b/g/n/ac is proposed, which is basically preamble based and can adaptively compensate for the discrepancy between transmitter and receiver radio frequency performances by exploiting the acknowledgment signal. The target system is a 1 × 1 wireless local area network chip with no null data packet or sounding. The algorithm can be supplemented by automatic rate fallback at the initial phase to further expedite rate adaptation. The target system receives wireless channel coefficients and previous packet information, translates them to amended signal-to-noise ratios, and then, via the mean mutual information, selects the modulation and coding scheme with the maximum throughput. Extensive simulation and wireless tests are carried out to demonstrate the validity of the proposed adaptive preamble-based link adaptation in comparison with both the popular automatic rate fallback and ideal link adaptation. The throughput gain of the proposed link adaptation over automatic rate fallback is demonstrated over various packet transmission intervals and Doppler frequencies. The throughput gain of the proposed algorithm over ARF is 46% (15%) for a 1-tap (3-tap) channel over 10 m–250 m (16 m–160 m) normalized Doppler frequencies. Assuming a 3-tap channel and 30 m–50 m normalized Doppler frequencies, the throughput of the proposed algorithm is about 31 Mbps, nearly the same as that of ideal link adaptation, whereas the throughput of ARF is about 24 Mbps, leading to a 30% throughput gain of the proposed algorithm over ARF. The firmware is implemented in C and on Xilinx Zynq 7020 (Xilinx, San Jose, CA, USA) for wireless tests.
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Marconi, Giovanni, Cristina Papayannidis, Maria Chiara Fontana, et al. "Alterations in Pathways Regulating Phosphatidil Inositol 3 Phosphate (PI3P) Produce Both Cell Proliferation and Therapy Resistance, and Define a Group of Patients with Poor Prognosis in Acute Myeloid Leukemia (AML)." Blood 128, no. 22 (2016): 1679. http://dx.doi.org/10.1182/blood.v128.22.1679.1679.
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Abstract Introduction PI3P is a key regulator of cell growth, and mediates cell proliferation via PI3K/AKT/mTOR in response to various growth signals. Abnormal activation of genes in its pathway is associated to oncogenic activity and poor Overall Survival (OS). PI3P is also a core activator of autophagy. Which role autophagy plays in cancer is not well established; it can function as a pro-apoptotic mechanism, or it can improve survive to stresses clearing damaged mitochondria and proteins accumulation, preventing apoptosis. Levels and activity of pro-apoptotic and anti-apoptotic proteins, particularly bcl-2 and p53, membrane signaling via mTOR, high levels of cAMP, a complex made by pink/park, promote a switch from apoptotic autophagy toward a mechanism that augment cell resiliency. Our study aims to define the role of PI3P pathways in AML, and to establish if autophagy could reduce the patients' chance to respond to induction, and to worsen OS. Methods We analyzed 208 consecutive newly diagnosed non M3 AML patients, screened for TP53, FLT3, NMP1, IDH1, IDH2, and DNMT3A mutations. Remission status was assessed with bone marrow biopsy. In all the patients, we perform Microarray-based Comparative Genomic Hybridization with Affymetrix SNP array 6.0 or Cytoscan HD; we perform Whole Exome Sequencing (WES)in 80/208 patients. Survival data were collected prospectively, with a median follow-up of 18 months. Survival analysis was performed with Kaplan Meyer method using log rank test. Univariate and multivariable regression and Cox Hazard Ratio(HR) model was performed. Correlation between variables was assessed with Fisher's exact test. Results We analyzed 4 pathways (Table 1); we selected genes in pathways basing on literature and GO data. Alterations in these pathways involved 103/209 patients (48%). PI3K/AKT/mTOR pathway alterations (both gains or losses) were shown to confer worst OS (p = .035, Figure 1a) when compared with unaltered patients; events in these pathways did not affect therapy response. Autophagy pathway alterations were shown to confer worst OS (p<.001, Figure 1b); alterations of autophagy were related to lower Complete Remission rate (CR%) after induction in univariate (p<.001) and multivariable regrassion with age, karyotype, secondary AML, TP53 mutation (p=0.014). Autophagy was significantly altered in patients with complex karyotype and TP53 mutation (p<.001). AMPK pathway alterations were shown to confer worst OS (p<.001, Figure 1c); Alteration of regulators in cAMP were related to lower CR% after induction in univariate (p<.001) and multivariable analysis with age, karyotype, secondary AML, TP53 mutation (p=0.009). AMPc pathway alteration was significantly associated with complex karyotype and TP53 mutation (p<.001). Autophagy switch pathway confer worst OS to patients(p<.001, figure 1d); autophagy switch was related to lower CR% after induction in univariate (p<.001) and multivariable analysis with age, karyotype, secondary AML (p<0.001). Autophagy switch was an independent risk factor in optimal Cox-HR model (p<.001, HR 2.996, CI 95% 2.101-4.271). Alterations in PINK or PARK did not showed to affect prognosis alone. Having at least an altered pathway is associated with worst prognosis (p <.001), and poor CR% after induction in univariate(p=.009) and multivariable analysis (p=.014). WES in a sub-cohort of patients did not found any significant mutation in genes we analyzed. This data is consistent with literature. Conclusions Our work investigates for the first time the role of PI3P pathways and autophagy in AML. Surprisingly, it showed that both positive and negative alterations in these pathways are associated with poor prognosis. Significantly, alterations in cAMP and autophagy pathways were associated with therapy resistance. These results point out that both positive and negative regulation of autophagy could worsen patients OS; a diminished autophagy could be linked to a hyper-proliferative state via activation of AKT/mTOR but an augmented autophagy could give cell resiliency, favoring cytoplasm turnover, damaged mitochondria elimination, and neutralizing oxidative damages to proteins. A pan-PI3K inhibitor could target these mechanisms and improve chemo-sensitivity in high risk AML. Acknowledgment: ELN, AIL, AIRC, PRIN, Progetto Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project. Disclosures Guadagnuolo: CellPly S.r.l.: Employment. Soverini:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Martinelli:Novartis: Speakers Bureau; MSD: Consultancy; Ariad: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Genentech: Consultancy; Roche: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.
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Rajbongshi, Aditya, Thaharim Khan, Md Mahbubur Rahman, Anik Pramanik, Shah Md Tanvir Siddiquee, and Narayan Ranjan Chakraborty. "Recognition of mango leaf disease using convolutional neural network models: a transfer learning approach." Indonesian Journal of Electrical Engineering and Computer Science 23, no. 3 (2021): 1681. http://dx.doi.org/10.11591/ijeecs.v23.i3.pp1681-1688.
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<p>The acknowledgment of plant diseases assumes an indispensable part in taking infectious prevention measures to improve the quality and amount of harvest yield. Mechanization of plant diseases is a lot advantageous as it decreases the checking work in an enormous cultivated area where mango is planted to a huge extend. Leaves being the food hotspot for plants, the early and precise recognition of leaf diseases is significant. This work focused on grouping and distinguishing the diseases of mango leaves through the process of CNN. DenseNet201, InceptionResNetV2, InceptionV3, ResNet50, ResNet152V2, and Xception all these models of CNN with transfer learning techniques are used here for getting better accuracy from the targeted data set. Image acquisition, image segmentation, and features extraction are the steps involved in disease detection. Different kinds of leaf diseases which are considered as the class for this work such as anthracnose, gall machi, powdery mildew, red rust are used in the dataset consisting of 1500 images of diseased and also healthy mango leaves image data another class is also added in the dataset. We have also evaluated the overall performance matrices and found that the DenseNet201 outperforms by obtaining the highest accuracy as 98.00% than other models.</p>
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Xu, Gang, and Liang Ma. "Resilient Self-Triggered Control for Voltage Restoration and Reactive Power Sharing in Islanded Microgrids under Denial-of-Service Attacks." Applied Sciences 10, no. 11 (2020): 3780. http://dx.doi.org/10.3390/app10113780.
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This paper addresses the problem of voltage restoration and reactive power sharing of inverter-based distributed generations (DGs) in an islanded microgrid subject to denial-of-service (DoS) attacks. Note that DoS attacks may block information exchange among DGs by jamming the communication network in the secondary control level of a microgrid. A two-layer distributed secondary control framework is presented, in which a state observer employing the multiagent system (MAS)-based ternary self-triggered control is implemented for discovering the average information of voltage and reactive power in a fully distributed manner while highly reducing communication burden than that the periodic communication way. The compensation for the reference signal to the primary control is acquired according to the average estimates to achieve voltage restoration while properly sharing reactive power among DGs. An improved ternary self-triggered control strategy integrating an acknowledgment (ACK)-based monitoring mechanism is established, where DoS attacks are modeled by repeated cycles of jamming and sleeping. A new triggering condition is developed to guarantee the successful information exchange between DGs when the sleep period of DoS attacks is detected. Using the Lyapunov approach, it is proved that the proposed algorithm allows agents to reach consensus regardless of the frequency of the DoS attacks, which maintains the accurate estimation of average information and the implementation of the secondary control objectives. The performance of the proposed control scheme is evaluated under simulation and experimental conditions. The results show that the proposed secondary control scheme can highly reduce the inter-agent communication as well as improve the robustness of the system to resist DoS attacks.
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Liberati, Elisa Giulia, Mara Gorli, and Giuseppe Scaratti. "Reorganising hospitals to implement a patient-centered model of care." Journal of Health Organization and Management 29, no. 7 (2015): 848–73. http://dx.doi.org/10.1108/jhom-07-2014-0129.
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Purpose – The purpose of this paper is to understand how the introduction of a patient-centered model (PCM) in Italian hospitals affects the pre-existent configuration of clinical work and interacts with established intra/inter-professional relationships. Design/methodology/approach – Qualitative multi-phase study based on three main sources: health policy analysis, an exploratory interview study with senior managers of eight Italian hospitals implementing the PCM, and an in-depth case study that involved managerial and clinical staff of one Italian hospital implementing the PCM. Findings – The introduction of the PCM challenges clinical work and professional relationships, but such challenges are interpreted differently by the organisational actors involved, thus giving rise to two different “narratives of change”. The “political narrative” (the views conveyed by formal policies and senior managers) focuses on the power shifts and conflict between nurses and doctors, while the “workplace narrative” (the experiences of frontline clinicians) emphasises the problems linked to the disruption of previous discipline-based inter-professional groups. Practical implications – Medical disciplines, rather than professional groupings, are the main source of identification of doctors and nurses, and represent a crucial aspect of clinicians’ professional identity. Although the need for collaboration among medical disciplines is acknowledged, creating multi-disciplinary groups in practice requires the sustaining of new aggregators and binding forces. Originality/value – This study suggests further acknowledgment of the inherent complexity of the political and workplace narratives of change rather than interpreting them as the signal of irreconcilable perspectives between managers and clinicians. By addressing the specific issues regarding which the political and workplace narratives clash, relationship of trust may be developed through which problems can be identified, mutually acknowledged, articulated, and solved.
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Shah, Hurmat Ali, and Insoo Koo. "Reliable Machine Learning Based Spectrum Sensing in Cognitive Radio Networks." Wireless Communications and Mobile Computing 2018 (September 12, 2018): 1–17. http://dx.doi.org/10.1155/2018/5906097.
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Spectrum sensing is of crucial importance in cognitive radio (CR) networks. In this paper, a reliable spectrum sensing scheme is proposed, which uses K-nearest neighbor, a machine learning algorithm. In the training phase, each CR user produces a sensing report under varying conditions and, based on a global decision, either transmits or stays silent. In the training phase the local decisions of CR users are combined through a majority voting at the fusion center and a global decision is returned to each CR user. A CR user transmits or stays silent according to the global decision and at each CR user the global decision is compared to the actual primary user activity, which is ascertained through an acknowledgment signal. In the training phase enough information about the surrounding environment, i.e., the activity of PU and the behavior of each CR to that activity, is gathered and sensing classes formed. In the classification phase, each CR user compares its current sensing report to existing sensing classes and distance vectors are calculated. Based on quantitative variables, the posterior probability of each sensing class is calculated and the sensing report is classified into either representing presence or absence of PU. The quantitative variables used for calculating the posterior probability are calculated through K-nearest neighbor algorithm. These local decisions are then combined at the fusion center using a novel decision combination scheme, which takes into account the reliability of each CR user. The CR users then transmit or stay silent according to the global decision. Simulation results show that our proposed scheme outperforms conventional spectrum sensing schemes, both in fading and in nonfading environments, where performance is evaluated using metrics such as the probability of detection, total probability of error, and the ability to exploit data transmission opportunities.
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Дремина, Наталья, Nataliya Dremina, Ирина Шурыгина, et al. "PATHOMORPHOLOGICAL DIAGNOSTICS OF CHRONIC APPENDICITIS." Acta biomedica scientifica 2, no. 5 (2018): 74–77. http://dx.doi.org/10.12737/article_5a3a0dda34db64.80244378.
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The review is devoted to the problem of diagnostics and differential diagnostics of chronic appendicitis. As it is commonly
 known, the very existence of chronic appendicitis is still considered controversial. The article describes the current ideas
 on chronic appendicitis (primary, secondary, residual and recurrent), presents the list of morphological manifestations
 in the vermiform appendix at chronic inflammation, discovered at routine histological examination: dystrophic changes
 in the form of atrophy of all layers of appendix with sclerosis or hypotrophy of various degree, up to appendiclausis
 and disappearance of mucous membrane, and lipomatosis of submucosa. The authors discuss the complexity of diag-
 nostics predetermined by lack of precise criteria of the disease; show the possibility of evaluation of the expression of
 cytoadherence molecules for diagnostics of the disease, in particular of VCAM-1 and ICAM-1 for differential diagnostics
 of chronic appendicitis. The role of suppressor of signal cytokine proteins SOCS3 in chronic inflammation is discussed.
 The data demonstrate the increase of T-lymphocytes and neurons in chronic appendicitis as an increase of PGP 9.5
 (panneuronal marker protein gene product 9.5) level. It has been shown, that immunohistochemical staining on p44
 MAPK has an advantage in differential diagnostics of chronic appendicitis – specific staining of subserous and muscle
 layer of the wall is observed only at the discussed pathology of the appendix.
 In spite of multiple studies and acknowledgment of the fact that chronic form of appendicitis is a separate disease,
 the diagnostics of this pathology still presents quite a problem especially when only routine methods of examination
 are used. Thus, we found it necessary to introduce additional immunomorphologic methods into the clinical practice.
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Boeva, Vasilisa, Yuri Voskoboinikov, and Rustam Mansurov. "Non-parametric identification of thermal control system elements." Analysis and data processing systems, no. 1 (March 26, 2021): 7–20. http://dx.doi.org/10.17212/2782-2001-2021-1-7-20.
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The thermal control system “Heater-Fan-Room” is represented by three different-type interconnected simpler subsystems. In this paper, a “black-box” whose structure is not specified is used as a mathematical model of the system and subsystems due to complexity of physical processes proceeding in these subsystems. For stationary linear systems, the connection between an input and an output of the “black-box” is defined by the Volterra integral equation of the first kind with an undetermined difference kernel also known as impulse response in the automatic control theory. In such a case, it is necessary to evaluate an unknown impulse response to use the “black-box” model and formulate all subsystems and the system as a whole. This condition complicates significantly the solution search of non-parametric identification problems in the system because an output of one subsystem is an input of another subsystem, so active identification schemes are unappropriated. Formally, an impulse response evaluation is a solution of the integral equation of the first kind for its kernel by registered noise-contaminated discrete input and output values. This problem is ill-posed because of the possible solution instability (impulse response evaluation in this case) relative to measurement noises in initial data. To find a unique stable solution regularizing algorithms are used, but the specificity of the impulse response identification experiment in the “Heater-Fan-Room” system do not allow applying computational methods of these algorithms (a system of linear equations or discrete Fourier transformation). In this paper, the authors propose two specific identification algorithms for complex technical systems. In these algorithms, impulse responses are evaluated using first derivatives of identified system signals that are stably calculated by smoothing cubic splines with an original smoothing parameter algorithm. The results of the complex “Heater-Fan-Room” system modeling and identification prove the efficiency of the algorithms proposed. Acknowledgments: The reported study was funded by RFBR, project number 20-38-90041.
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Ding, Wei, Tait D. Shanafelt, Connie Lesnick, et al. "Allosteric Akt Inhibitor MK2206 Synergizes with Bendamustine in Promoting the Apoptosis of Chronic Lymphocytic Leukemia Cells and Selectively Targets B-Cell Receptor Mediated Cytokine Production." Blood 120, no. 21 (2012): 3928. http://dx.doi.org/10.1182/blood.v120.21.3928.3928.
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Abstract Abstract 3928 Background: Accumulating data support the critical role of PI3K/Akt in CLL B cell receptor (BCR) mediated signal transduction, cell proliferation and survival. In addition recent preclinical and clinical studies indicate that specific PI3K blockade results in robust preclinical and clinical efficacy in CLL. In our model system of CLL B cell-stromal cultures which feature their interaction, platelet derived growth factor (PDGF) present in CLL culture medium drives VEGF production through PI3K/Akt activation in stromal cells (Blood. 2010. 116:2984). Indeed Akt was found to be activated in leukemic cells during the CLL-stroma interaction (Leuk Res. 2008. 32:1565). Therefore, we hypothesized that Akt inhibition should promote CLL B cell apoptosis and abrogate BCR mediated cytokine production. MK2206 is an orally bioavailable highly specific allosteric Akt inhibitor. It has been tested in patients with refractory solid tumors and was demonstrated to be safely administered in a phase I trial. Therefore the goal of this study was to test the preclinical efficacy of MK2206 on both the survival and the BCR mediated cytokine production of CLL leukemic B cells. Methods: Peripheral blood mononuclear cells isolated from CLL patients (n=37) were treated with escalating concentrations of MK2206 (1–16 μM) for 24 hours, 48 hours or 72 hours. The levels of leukemic B cell viability were tested using an (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay. The potential impact (antagonistic/additive/synergistic) of Bendamustine in combination with MK2206 was also tested by using the MTT assay. We used the Calcusyn system to calculate the effect of drug interactions. The combination index (CI) as calculated by the program usually indicates synergy when ≤ 0.8 and indicates additive outcomes when between 0.8–1.2. A CI >1.2 indicates antagonism. Downstream signals of Akt activation in CLL B cells were evaluated by testing their expression of Mcl-1, 4EBP1 and p70S6K using immunoblot. The impact of Akt inhibition by MK2206 on cytokine production in response to B-cell receptor ligation with anti-IgM was also tested using a multiplex cytokine analysis (Invitrogen) in a time-course experiment. Results: MK2206 treatment induced concentration- and time-dependent apoptosis in CLL leukemic cells. At 72 hours, the IC50 of MK2206 in the experiments using CLL leukemic cells in vitro is ∼8 mM. MK2206 incubation at 1 or 5 mM cultured with CLL B cells over a 48-hour period abolished of Akt and p70S6K phosphorylation while native PARP was cleaved into the 85 kD polypeptide fragment. However, the expression level of the upstream signal molecule, PI3K, was not changed. Among the CLL patients tested (n = 37), we did not find any difference in sensitivity to MK2206 induced apoptosis based on critical prognostic factors of CD38, ZAP-70, IGHV and del(17p) status. Importantly, we detected synergistic or additive activity between MK2206 and Bendamustine in 11 tested CLL samples when these combinations were used to treat CLL cells in vitro for 72hrs. Thus the median CI value for this group of patients was 0.8 (0.1 – 1.1). Six were found to have CI ≤ 0.8 and five fell within the additive CI values (0.8 – 1.2). Production of immune or chemotactic cytokines (e.g. CCL3, CCL4, MCP-1, IL-1Ra, IL-8 and IL-2R) at 24 hour incubation increased significantly above baseline when CLL cells were stimulated anti-IgM. Akt inhibition with MK2206 selectively abrogated upregulation of CCL3, CCL4, MCP-1 and IL-2R production, but not for IL-8 or IL-1Ra secretion. MK2206 also abolished BCR mediated Akt activation and decreased Erk activation. Conclusion: MK2206, a robust and selective Akt inhibitor, induced significant in vitro apoptosis of CLL B-cells in vitro. Preclinical evidence of a synergistic effect between MK2206 and Bendamustine was also observed independent of prognostic risk. MK2206 abolished BCR mediated Akt activation and selectively abrogates BCR mediated production of cytokines that may promote apoptotic resistance. These findings support the use of MK2206 in treating CLL and indeed we have initiated a phase I/II trial of MK2206 in combination with Bendamustine and Rituximab for relapsed CLL patients(N1087, October 2011). Acknowledgments: This study was funded by the NCI-K23, NCCTG and CLL Global Foundation. Disclosures: Shanafelt: Cephalon: Research Funding; Genentech: Research Funding. Kumar:Genzyme: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Honoraria. Kay:Celgene: Research Funding.
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Gupta, Vaibhav, John A. Sellers, Charles D. Ellis, et al. "Minimizing Film Stress and Degradation in Thin-Film Niobium Superconducting Cables." Additional Conferences (Device Packaging, HiTEC, HiTEN, and CICMT) 2017, DPC (2017): 1–25. http://dx.doi.org/10.4071/2017dpc-tha3_presentation4.
Full textAbstract:
The future of superconducting and cryogenic electronic systems can significantly benefit from densely integrated superconducting multi-layer and multi-signal flexible cables due to the massive number of electrical interconnects needed in systems such as superconducting quantum computers and cryogenic detector arrays. In order to maintain superconductivity in niobium (Nb) thin films, film stress and degradation must be minimized. We are working towards configurations with embedded traces, where it is expected that the superconductor material will be subjected to subsequent fabrication steps that must not degrade the properties of the superconductor. We previously observed degradation of the superconducting properties of Nb, such as reduction of both transition temperature and critical current, as a result of curing a polyimide passivation layer at supplier recommended curing temperature (350 oC). The deterioration in the superconducting properties may be due to mechanical stress in the film or diffusion of impurities into the Nb during the curing process Film stress plays a vital role in the superconducting properties of Nb. Previous research by other groups has focused on in situ ion bombardment, substrate fixturing and wafer preparation in order to minimize film stress. In this work, we discuss the role of argon (Ar) pressure and power during Nb sputtering on the quality of Nb and Nb/Al thin films. By varying the Ar pressure and applied power during sputter deposition, we have produced both tensile and compressive films on flexible substrates in order to find the pressure that yields a near zero stress Nb and Nb/Al thin film at room temperature. A low stress Nb film was tested with a thin Al barrier layer (of the order of 10's of nm) between Nb and polyimide to protect the Nb superconductivity during the PI curing step. Nb traces with a thickness of roughly 250nm and a width of 50um were used for this work. Nb films deposited at different Ar pressures and power levels were tested for critical transition temperature (Tc), critical current (Ic), and sheet resistance (Ω/□), to compare the superconducting behavior of different Nb films. Details of the fabrication processes, experimental procedures and performance results will be presented. This work will help determine materials stacks-ups that may be useful for future multi-layer Nb-based flexible superconducting cables. Acknowledgment: We gratefully acknowledge financial support and technical guidance from Microsoft Research for this work.
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Alberti, S., M. Trerotola, R. Dell’ Arciprete, et al. "Selective killing of human cancer cells by targeting a fusion mRNA between CYCLIN D1 and TROP2." Journal of Clinical Oncology 27, no. 15_suppl (2009): e14569-e14569. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14569.
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e14569 Background: Trop-2 is a calcium signal transducer and a stem cell marker. Trop-2 is widely overexpressed by human cancers and stimulates their growth. A TROP2 mRNA was isolated as post-transcriptionally joined to CYCLIN D1 transcripts, suggesting this as one of the transforming mechanisms of TROP2. Methods: In vitro cell growth assays were utilized to assess the cell growth stimulatory capacity of the chimeric mRNA. Colony assays for growth in soft agarose and tumorigenicity assays in nude mice were utilized to assess for the transforming capacity of the fusion transcript. siRNA constructs were utilized for the stably shut-down of the expression of the CYCLIN D1-TROP2 mRNA. Results: The chimeric mRNA transforms primary cells in vitro and induces aggressive tumor growth in vivo in cooperation with activated RAS. The CYCLIN D1-TROP2 mRNA is expressed by a large fraction of human ovarian, endometrial and gastro-intestinal tumors. The chimera is coexpressed with activated RAS in a subset of tumors, consistent with a cooperative transforming activity. The chimeric mRNA is a bicistronic transcript that independently translates wild type Cyclin D1 and Trop-2 proteins, i.e. it does not generate chimeric, oncogenic proteins. On the other hand, joining to the stable TROP2 mRNA leads to a higher CYCLIN D1 mRNA stability, with inappropriate persistence during the cell cycle and acquisition of transforming capacity. As essentially no normal tissues express the chimeric mRNA, we targeted it for destruction in cancer cells with stably expressed siRNA constructs. Specific targeting led to essential annnihilation of the CYCLIN D1-TROP2 mRNA, in the absence of off-target effects. Silencing of the chimeric mRNA blocked the growth of expressing breast cancer cells. Conclusions: Our findings demonstrate a novel, widespread oncogenic mechanism in human cancers, and open novel avenues for mRNA-targeted anti-cancer therapies. Acknowledgments This work was supported by the the Fondazione of the Cassa di Risparmio della Provincia di Chieti, the Association for the Application of Biotechnology in Oncology (ABO and ABO Project S.p.A., grant no. VE01D0019) and the Marie Curie Transfer of Knowledge Fellowship, contract number 014541. No significant financial relationships to disclose.
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BUCK, MATTHIAS. "Trifluoroethanol and colleagues: cosolvents come of age. Recent studies with peptides and proteins." Quarterly Reviews of Biophysics 31, no. 3 (1998): 297–355. http://dx.doi.org/10.1017/s003358359800345x.
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Alcohol based cosolvents, such as trifluoroethanol (TFE) have been used for many decades to denature proteins and to stabilize structures in peptides. Nuclear magnetic resonance spectroscopy and site directed mutagenesis have recently made it possible to characterize the effects of TFE and of other alcohols on polypeptide structure and dynamics at high resolution. This review examines such studies, particularly of hen lysozyme and β-lactoglobulin. It presents an overview of what has been learnt about conformational preferences of the polypeptide chain, the interactions that stabilize structures and the nature of the denatured states. The effect of TFE on transition states and on the pathways of protein folding and unfolding are also reviewed. Despite considerable progress there is as yet no single mechanism that accounts for all of the effects TFE and related cosolvents have on polypeptide conformation. However, a number of critical questions are beginning to be answered. Studies with alcohols such as TFE, and ‘cosolvent engineering’ in general, have become valuable tools for probing biomolecular structure, function and dynamics.1. COSOLVENTS: OLD HAT? 2982. HOW DOES TFE WORK? 2992.1 Effect on hydrogen bonding 3002.2 Effect on non-polar sidechains 3012.3 Effect on solvent structure 3023. EFFECTS OF TFE ON (UN-)FOLDING TRANSITIONS 3033.1 Pretransition 3033.2 Transition 3043.3 Posttransition 3053.4 Far UV CD spectroscopic detection of structure 3063.5 Effect with temperature 3063.6 Effect with additional denaturants 3064. THERMODYNAMIC PARAMETERS FROM STRUCTURAL TRANSITIONS OF PEPTIDES AND PROTEINS IN TFE 3075. ADVANCES IN NMR SPECTROSCOPY 3105.1 Chemical shifts 3105.2 3[Jscr ]HNHαcoupling constants 3115.3 Amide hydrogen exchange 3125.4 Nuclear Overhauser Effects (NOEs) 3126. α-HELIX – EVERYWHERE? 3136.1 Intrinsic helix propensity equals helix content? 3136.2 A helix propensity scale for the amino acids in TFE 3146.3 Capping motifs and stop signals 3156.4 Limits and population of helices as seen by CD and NMR 3167. TURNS 3178. β-HAIRPINS AND SHEETS 3179. ‘CLUSTERS’ OF SIDECHAINS 32010. THE TFE DENATURED STATE OF β-LACTOGLOBULIN 32111. THE TFE DENATURED STATE OF HEN LYSOZYME 32412. TERTIARY STRUCTURE, DISULPHIDES, DYNAMICS AND COMPACTNESS 32713. PROSPECTS FOR STRUCTURE CALCULATION 32814. EFFECT OF TFE ON QUATERNARY STRUCTURE 32915. EFFECT ON TFE ON UN- AND REFOLDING KINETICS 33016. OTHER USES 33616.1 Mimicking membranes and protein receptors 33616.2 Solubilizing peptides and proteins 33616.3 Cosolvents as helpers for protein folding? 33816.4 Modifying protein dynamics and catalysis 33816.5 Effects on nucleic acids 33916.6 Effects on lipid bilayers and micelles 33916.7 Future applications 33917. CONCLUSIONS: TFE – WHAT IS IT GOOD FOR? 34018. ACKNOWLEDGMENTS 34019. REFERENCES 340
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Dementyeva, Elena, Fedor Kryukov, Sabina Sevcikova, et al. "Association Study of Ploidy Category with Mitotic Disruption In Multiple Myeloma." Blood 116, no. 21 (2010): 2952. http://dx.doi.org/10.1182/blood.v116.21.2952.2952.
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Abstract Abstract 2952 Background Centrosome aberrations are common in many types of human malignancies and are associated with aneuploidy. Loss of centrosome duplication control will often create multipolar spindles that in turn could be responsible for incorrect segregation of whole chromosomes leading to aneuploidy. Hyperdiploidy (subtype of aneuploidy) is one of the most frequent cytogenetic abnormalities in multiple myeloma (MM), where molecular changes are among the primary genetic events in disease pathogenesis. But no correlation between centrosome aberrations and aneuploidy in MM has ever been found. Aims The objective of our study was to evaluate association of MM ploidy category with centrosome amplification in both B and plasma cells subpopulations and to investigate structural defects (gain/loss) and gene expression changes in genes controlling centrosome numbers. Methods Immunofluorescent labeling was used for evaluation of centrosome amplification (CA) in B-cells (CD19+) and PCs (CD138+) of MM patients. Centrin (centrosome protein) copy numbers were used to define presence of centrosome amplification (CA) in cells: cells with more than 4 signals of centrin were considered to be positive. Samples with ≥11% of B-cells or ≥10% of PCs with >4 fluorescence signals of centrin were considered as CA positive. A total of 140 patients were evaluated for CA in PCs and/or B-cells, including 50 patients where both cell types were analyzed. The patient population characteristics were as follows: males/females 67/73, median age of 66 years (range, 40–92 years). Newly diagnosed (52/140) and relapsed (88/140) patients were included in this study; most of them had advanced stage of MM (DS II/III n = 107; ISS II/III n = 92). Interphase FISH with cytoplasmic immunoglobulin light chain staining (cIg FISH), oligonucleotide-based arrayCGH (20 patients) and qRT-PCR (5 CA positive vs 5 CA negative patients) were performed on plasma cells. Hyperdiploidy analysis was done using Multi-Color Probe Panel (LSI D5S23/D5S721, CEP 9 and CEP 15) for chromosome 5, 9 and 15. Only cells with three or more signals from at least two of three investigated chromosomes were classified as hyperdiploid. ArrayCGH and qRT-PCR were focused on chosen list of mitotic genes, according to their role in normal centrosome duplication process. Results The frequency of MM cases positive for CA was 35% (35/100) and 39% (32/82), based on the analysis of PC samples and B-cell samples, respectively. Overall, 18% (9/50) of MM patients were double-positive. Presence of centrosome amplification in B-cells of MM patients was established in our previous study. Significant correlation of centrosome amplification in PCs with hyperdiploidy was not found. But association of CA in B-cells with PCs hyperdiploidy using phi 4-point correlation was proven (phi=0.358, p<0.05). In group of newly diagnosed patients (52/140), this correlation was much stronger (phi=0.555, p<0.05). ArrayCGH analysis of genes controlling centrosome duplication did not show correlation between their copy number defects and hyperdiploidy in myeloma cells. As for gene expression analysis, significant differences were found in levels of ARKA and PCNT genes (p<0.05). Relative quantification coefficient R of these genes was two times higher in CA positive patients when compared to CA negative patients. No significant correlation between amount of CA positive PCs and B-cells was found (p>0.05). But after splitting patients based on CA threshold, significant correlation was identified (r=-0,763, p=0.017) in double-positive group. Conclusion In our study, we show association of CA in B-cells with PCs hyperdiploidy. This finding relates to the role of B-cell mitotic disruption in MM aneuploidy and cell carcinogenesis. It gives us a possibility to suspect the impact of abnormal B cells in myeloma cells development. B-cells with CA probably enter mitosis but do not finish it properly resulting in aneuploid cells; these cells may represent an aneuploid pool of MM cells. Acknowledgments This study was supported by grants MSM 0021622434 and IGA 10207-3 from the Departments of Education and Health of the Czech Republic. Disclosures: No relevant conflicts of interest to declare.
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Khan, Malak Abid Ali, Hongbin Ma, Syed Muhammad Aamir, and Ying Jin. "Optimizing the Performance of Pure ALOHA for LoRa-Based ESL." Sensors 21, no. 15 (2021): 5060. http://dx.doi.org/10.3390/s21155060.
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(1) Background: The scientific development in the field of industrialization demands the automization of electronic shelf labels (ESLs). COVID-19 has limited the manpower responsible for the frequent updating of the ESL system. The current ESL uses QR (quick response) codes, NFC (near-field communication), and RFID (radio-frequency identification). These technologies have a short range or need more manpower. LoRa is one of the prominent contenders in this category as it provides long-range connectivity with less energy harvesting and location tracking. It uses many gateways (GWs) to transmit the same data packet to a node, which causes collision at the receiver side. The restriction of the duty cycle (DC) and dependency of acknowledgment makes it unsuitable for use by the common person. The maximum efficiency of pure ALOHA is 18.4%, while that of slotted ALOHA is 36.8%, which makes LoRa unsuitable for industrial use. It can be used for applications that need a low data rate, i.e., up to approximately 27 Kbps. The ALOHA mechanism can cause inefficiency by not eliminating fast saturation even with the increasing number of gateways. The increasing number of gateways can only improve the global performance for generating packets with Poisson law having a uniform distribution of payload of 1~51 bytes. The maximum expected channel capacity usage is similar to the pure ALOHA throughput. (2) Methods: In this paper, the improved ALOHA mechanism is used, which is based on the orthogonal combination of spreading factor (SF) and bandwidth (BW), to maximize the throughput of LoRa for ESL. The varying distances (D) of the end nodes (ENs) are arranged based on the K-means machine learning algorithm (MLA) using the parameter selection principle of ISM (industrial, scientific and medical) regulation with a 1% DC for transmission to minimize the saturation. (3) Results: The performance of the improved ALOHA degraded with the increasing number of SFs and as well ENs. However, after using K-mapping, the network changes and the different number of gateways had a greater impact on the probability of successful transmission. The saturation decreased from 57% to 1~2% by using MLA. The RSSI (Received Signal Strength Indicator) plays a key role in determining the exact position of the ENs, which helps to improve the possibility of successful transmission and synchronization at higher BW (250 kHz). In addition, a high BW has lower energy consumption than a low BW at the same DC with a double-bit rate and almost half the ToA (time on-air).
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Simdiankin, Arkadii A., Alexandr М. Davydkin, Mikhail N. Slyusarev, and Alexander М. Zemskov. "Evaluation of the Influence of Motor Oil Ultrasonic Processing on the Wear of Friction Pairs during Long-Term Wearing Tests." Mordovia University Bulletin, no. 4 (December 28, 2018): 583–602. http://dx.doi.org/10.15507/0236-2910.028.201804.583-602.
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Introduction. The influence of ultrasound parameters on the properties of processed lubricating oils and wear characteristics of friction pairs is a relevant problem in agricultural engineering. The paper presents a simple method for influencing on the lubricating oil by ultrasonic vibrations of the optimum frequency and power that results in reducing the wear of the interfaces of mechanisms and machines. The authors study the change in the physical characteristics of the oil during its ultrasound treatment and the assessment of their effect on the wear of a friction pair during long-term tests. Materials and Methods. We used a generator with variable signal parameters, a lever scale, a burette and an alcohol thermometer to assess the change in coefficient of surface tension of engine oil during sonication. Long-term tribotechnical tests were carried out on 2070 CMT-1M friction machine according to the “roller ‒ pad” scheme. The mass of these samples after long-term tests was weighed by Sartorius company analytical scales with a measurement accuracy of 0.00001 g. A profilograph-profilometer of Taylor Hobson Company was also used. Results. As a result of the research, the optimum frequency and power of ultrasound were revealed for lubricating oil processing. The decrease in the surface tension coefficient of oil was more than 5 %. With prolonged wear tests, the wear factor was reduced by 28 %. Conclusions. The effect of increasing the wear resistance of friction pairs when exposed to ultrasound oil is associated with a decrease in its surface tension coefficient, which allows the oil to be distributed with minimal effort over the surfaces with forming a film of sufficient thickness, which increases the bearing capacity of rubbing surfaces. Keywords: wear, surface tension coefficient, motor oil, tribotechnical test, ultrasound For citation: Simdiankin A. A., Davydkin A. M., Slyusarev M. N., Zemskov A. M. Evaluation of the Influence of Motor Oil Ultrasonic Processing on the Wear of Friction Pairs during Long-Term Wearing Tests. Vestnik Mordovskogo universiteta = Mordovia University Bulletin. 2018; 28(4):583–602. DOI: https://doi.org/10.15507/0236-2910.028.201804.583-602 Acknowledgments: The study was conducted with the financial support of the Ministry of Education and Science of the Russian Federation (state task, direction: development of competencies) project no. 11.3416.2017/4.6 “Development of technologies and tools to improve the durability of parts, assemblies, machines and equipment by creating nanostructured coatings sources of concentrated energy”.
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Kim, H. R., K. A. Lee, S. H. Lee, and S. H. Kim. "SAT0214 ULTRASONOGRAPHIC CHANGES OF SALIVARY GLANDS IN PRIMARY SJOGREN’S SYNDROME: A LONGITUDINAL PROSPECTIVE STUDY." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 1050.2–1050. http://dx.doi.org/10.1136/annrheumdis-2020-eular.337.
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Background:In the diagnosis of primary Sjogren’ syndrome (SS), salivary gland ultrasound is useful tool. Until now, there is no data for ultasonographic changes of major salivary glands over time.Objectives:This study aimed to evaluate the changes in abnormalities of salivary gland ultrasound (SGUS) over time in patients with pSS.Methods:Patients with pSS (n=70) and idiopathic sicca syndrome (n=18) underwent SGUS twice at baseline and 2 years later. The semi-quantitative SGUS score (0-48) was used, which comprises five parameters: parenchymal echogenicity, homogeneity, hypoechoic areas, hyperechogenic reflections, and clearness of posterior borders. The intraglandular power Doppler signal (PDS) was also assessed. The changes of these SGUS variables were compared in patients with pSS and idiopathic sicca syndrome.Results:The median (interquartile range) total SGUS scores at baseline was 27 (14) in patients with and 4 (3) in those with idiopathic sicca syndrome (p<0.001). In the pSS group, the total SGUS scores and the SGUS scores for bilateral parotid glands were significantly increased during median 23.4 month follow-up (p=0.013 andp=0.011, respectively). Homogeneity and hypoechoic areas were the domain to show statistically significant progression of SGUS scores. None of the SGUS scores changed significantly in the patients with idiopathic sicca syndrome. In patients with pSS, baseline and follow-up PDS sum scores of four salivary glands were significant higher in worsening SGUS group (n=13) than no change/improvement SGUS group (n=55/2).Conclusion:The structural abnormalities in major salivary glands assessed using SGUS scores progressed significantly in patients with pSS. In pSS group, 18.6% patients had worsening SGUS scores during 2 years. Intra-glandular hypervascularity was associated with worsening of salivary gland abnormalities.References:[1]Delli K, Dijkstra PU, Stel AJ, Bootsma H, Vissink A, Spijkervet FK. Diagnostic properties of ultrasound of major salivary glands in Sjogren’s syndrome: a meta-analysis. Oral diseases. 2015;21(6):792-800.[2]Jousse-Joulin S, Devauchelle-Pensec V, Cornec D, Marhadour T, Bressollette L, Gestin S, et al. Brief Report: Ultrasonographic Assessment of Salivary Gland Response to Rituximab in Primary Sjogren’s Syndrome. Arthritis & rheumatology (Hoboken, NJ). 2015;67(6):1623-8.[3]Gazeau P, Cornec D, Jousse-Joulin S, Guellec D, Saraux A, Devauchelle-Pensec V. Time-course of ultrasound abnormalities of major salivary glands in suspected Sjogren’s syndrome. Joint, bone, spine: revue du rhumatisme. 2018;85(2):227-32.[4]Lee KA, Lee SH, Kim HR. Diagnostic and predictive evaluation using salivary gland ultrasonography in primary Sjogren’s syndrome. Clinical and experimental rheumatology. 2018;36 Suppl 112(3):165-72.Acknowledgments: :This work was funded by the Konkuk University Medical Center Research Grant 2019.Disclosure of Interests:None declared
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Rech, J., K. Tascilar, H. Schenker, et al. "SAT0050 PREDICTION OF RESPONSE TO CERTOLIZUMAB PEGOL TREATMENT BY FUNCTIONAL MRI OF THE BRAIN: AN INTERNATIONAL, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (PRECEPRA)." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 956.1–956. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4288.
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Background:Personalization of RA treatment is not optimal due to lack of predictors. We previously demonstrated in RA patients that central nervous system (CNS) pain response to tender joint compression, measured by using functional MRI (fMRI) of the brain rapidly wanes after 24 hours of anti-TNF administration and that a higher pre-treatment BOLD signal volume seems to predict clinical response to treatment with certolizumab-pegol (CZP)1,2. We therefore hypothesized that the CNS pain response upon compression of a painful joint could predict subsequent anti-TNF treatment response.Objectives:To compare disease activity after 12-weeks of CZP treatment to that of placebo in DMARD-refractory RA patients based on pre-treatment baseline CNS pain response measured using BOLD fMRI.Methods:Adult RA patients fulfilling the 2010 ACR/EULAR classification criteria with a DAS28>3.2 under stable DMARD treatment for at least 3 months were eligible. Patients underwent fMRI scanning of the brain at screening for stratification by CNS pain response. Whole brain BOLD-signal-voxel-count of 700 units classifying between low and high, and were randomized to CZP or placebo (2:1) The primary outcome was low disease activity (LDA, DAS28 ≤3.2) after 12 weeks of treatment.Results:156 RA patients, inadequate responders to csDMARD, signed the informed consent. 139 patients (46/47, 46/49 and 42/43) (99 females, 71%) with moderate-high disease activity (mean (SD) DAS-28: 4.83 (1.03)) could be included respectively and completed the 12-week study treatment. Geometric mean (SD) numbers of baseline BOLD signal positive voxels were 559 (10), 81 (12) and 2498 (3) in the 3 arms respectively. The mean DAS28 (SD) scores after 12 weeks of study treatment were Placebo: 3.89 (1.29), CZP-L: 3.42 (1.06) and CZP-H: 3.06 (1.04). LDA was achieved in 12/47 patients (25.5 %) in placebo, 22/49 (44.9%) in the CZP-L, and 25/43, (58.1%) in the CZP-H arm. The linear effect term for the ordinal study group variable supported a linear trend of increasing CZP treatment effect with increasing baseline CNS pain response. RR (95% CI) for achieving LDA with each unit increase in treatment category over placebo was 1.79 (1.24 to 2.74, p=0.003).Conclusion:A higher pre-treatment brain activity in response to pain measured with fMRI predicts the chance of achieving low disease activity with CZP treatment.References:[1] Hess, A.et al.PNAS (2011)[2] Rech, J.et al. Arthritis & Rheumatism(2013).Acknowledgments :The study was supported by an unrestricted grant from UCB Biopharma SPRL, Brussels, BelgiumDisclosure of Interests:Jürgen Rech Consultant of: BMS, Celgene, Novartis, Roche, Chugai, Speakers bureau: AbbVie, Biogen, BMS, Celgene, MSD, Novartis, Roche, Chugai, Pfizer, Lilly, Koray Tascilar: None declared, Hannah Schenker: None declared, Marina Sergeeva: None declared, Mageshwar Selvakumar: None declared, Laura Konerth: None declared, Jutta Prade: None declared, Sandra Strobelt: None declared, Melanie Hagen: None declared, Verena Schönau: None declared, Larissa Valor: None declared, Axel Hueber Grant/research support from: Novartis, Lilly, Pfizer, EIT Health, EU-IMI, DFG, Universität Erlangen (EFI), Consultant of: Abbvie, BMS, Celgene, Gilead, GSK, Lilly, Novartis, Speakers bureau: GSK, Lilly, Novartis, David Simon Grant/research support from: Else Kröner-Memorial Scholarship, Novartis, Consultant of: Novartis, Lilly, Arnd Kleyer Consultant of: Lilly, Gilead, Novartis,Abbvie, Speakers bureau: Novartis, Lilly, Frank Behrens Grant/research support from: Abbvie, Pfizer, Roche, Chugai, Janssen, Consultant of: Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; Sandoz, Speakers bureau: Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; Sandoz, José Antonio P. da Silva Grant/research support from: Pfizer, Abbvie, Consultant of: Pfizer, AbbVie, Roche, Lilly, Novartis, Christoph Baerwald Consultant of: CGB received speaker or consulting fees from AbbVie, Paid instructor for: CGB received speaker or consulting fees from AbbVie, Speakers bureau: CGB received speaker or consulting fees from AbbVie, Stephanie Finzel: None declared, Reinhard Voll: None declared, Eugen Feist Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Arnd Doerfler: None declared, Nemanja Damjanov Grant/research support from: from AbbVie, Pfizer, and Roche, Consultant of: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Speakers bureau: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Andreas Hess: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB
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Tan, Melanie, Gerben C. Mol, Marcel A. Van de Ree, et al. "Accuracy of Magnetic Resonance Direct Thrombus Imaging (MRDTI) As a Novel Tool in the Diagnosis of Acute Ipsilateral Recurrent Deep Vein Thrombosis." Blood 120, no. 21 (2012): 395. http://dx.doi.org/10.1182/blood.v120.21.395.395.
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Abstract Abstract 395 Background Accurate diagnostic assessment of suspected acute ipsilateral recurrent deep vein thrombosis (DVT) is of high clinical importance, however discriminating residual thrombosis from acute recurrent DVT may be challenging. It is known that in 32% of the patients with a suspected acute ipsilateral recurrent DVT the ultrasound examination are non-conclusive. Despite this, patients were treated with indefinite anticoagulant therapy, indicating overtreatment in this group of patients (Tan M et al. J Thromb Haemost 2010). A non-invasive MR technique (Magnetic Resonance Direct Thrombus Imaging (MRDTI), without need for intravenous contrast agent, showed high sensitivity and specificity for diagnosing a first acute DVT (Fraser et al Ann Intern Med 2002). Furthermore the high signal associated with acute thrombosis was not detected 6 months after the initial acute thrombosis, making MRDTI potential relevant for distinguishing a recurrent DVT from a residual thrombosis (Westerbeek RE et al J Thromb Haemost 2008). This study evaluated the accuracy of MRDTI in patients with an acute ipsilateral recurrent DVT and patients with residual thrombosis. Patients/Methods In total 84 patients were enrolled. Of these, 42 consecutive patients had an acute ipsilateral recurrent DVT according to the current ultrasound examination standards in combination with a positive D-dimer test (≥ 500 μg/L); all patients were treated with anticoagulants. Furthermore, 42 patients were without acute signs and symptoms, however had a residual thrombosis on ultrasound examination in combination with a negative D-dimer test (< 500 μg/L). All patients received a MR examination within 48 hours of presentation. MR images were assessed in a blinded fashion by two radiologists. Sensitivity, specificity and interobserver variability were calculated. Results The images of two patients with ipsilateral recurrent DVT were not interpretable, one patient had a knee prosthesis that gave artifacts and in the other patient not the venous system of interest was imaged. The images of 40 patients with an ipsilateral recurrent DVT and of 42 patients with residual thrombosis were fully interpretable. Sensitivity was 86% (95% CI, 71 –94%) and specificity was 100% (95% CI, 89–100%) for MRDTI by the first observer; sensitivity was 88% (95% CI, 74–96%) and specificity was 100% (89–100%) by the second observer. The interobserver agreement between both observers was excellent, with a kappa statistics of 0.97 (95% CI, 0.92 – 1.0). Conclusion Our study shows reasonable sensitivity and very good specificity figures with an excellent observer agreement for imaging an ipsilateral recurrent DVT and residual thrombosis with MRDTI. The sensitivity is somewhat lower than expected; a reason could be that patients with inconclusive ultrasounds were considered as acute recurrent thrombosis by the attending physician, while in fact they had a residual thrombosis. We conclude that MRDTI has good potential in distinguishing a residual thrombosis from an acute recurrent DVT and could therefore be of high value for the diagnosis of patients with suspected acute ipsilateral recurrent DVT. This should however be further evaluated in a management outcome study in which treatment decisions are based on the results of MR. Acknowledgment This study was supported by the Netherlands Heart Foundation (grant no. 2007B146) Disclosures: No relevant conflicts of interest to declare.
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Kasireddy, Nithya, Jeremy C. Orie, and Damir Khismatullin. "Resonant Acoustic Tweezing Spectroscopy for Small-Volume Noncontact Assessment of Blood Coagulation." Blood 132, Supplement 1 (2018): 3785. http://dx.doi.org/10.1182/blood-2018-99-117902.
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Abstract Introduction: Measurement and interpretation of mechanical properties of whole blood and blood plasma are important diagnosis and treatment monitoring of various conditions like coagulopathy, hemophilia, sickle cell disease and many cardiovascular disorders. Many of the current techniques like thromboelastography, micro-viscometry or microfluidic devices used for this purpose require a large sample volume and/or may be prone to measurement errors due to sample contact with device walls. To address these issues, we developed a single-drop non-contact method for blood rheological analysis, referred to as "acoustic tweezing rheometry". With sample volume as small as 4 μL, our innovative technology has been successfully applied for assessment of whole blood and blood plasma coagulation. Here, we present the extension of this technology to resonant spectroscopic measurement of blood viscoelasticity. Materials and Methods: The schematic of the acoustic tweezing device is shown in (Figure 1A). The standing acoustic wave field between the transducer and reflector generates the acoustic radiation force on the biological sample that traps it in a host fluid (e.g., air). Sample tweezing (force-induced deformation and translational motion of the trapped sample) is achieved by amplitude modulation of the acoustic tweezing signal at high frequency and then decrease the frequency continuously until the lower limit for sample trapping is reached. During this frequency sweep, shape changes of the sample were recorded (Figure 1B) by a photodetector and a high-speed camera (Figure 1A). The amplitude-frequency response of the sample was obtained from raw data analysis, with the amplitude being the maximum deflection of the sample height from its equilibrium value. Dynamic (shear) viscosity and elasticity of the sample were assessed from the quality factor of the amplitude-frequency response (Figure 1C) and the resonance frequency, respectively. Results and Discussion: The quality factor analysis predicted that the dynamic viscosity of commercial normal control blood plasma was 1.5 mPa·s at room temperature, which agreed with previous large-sample-volume measurements. Once re-calcified, the resonance frequency of blood plasma and thus its shear elasticity increased due to clot formation until reaching a plateau in 5 min (Figure 1D). Using this graphical output (referred to as "tweezograph"), the following coagulation parameters can be extracted: clot initiation time, clotting rate, clotting time, and maximum clot elasticity. Conclusions: Resonant acoustic tweezing spectroscopy can accurately measure dynamic viscosity and elasticity of whole blood and blood plasma with a small drop of the sample and without artefacts or measurement errors due to sample contact with device walls. This technique can be applied for rapid assessment of whole blood and blood plasma coagulation. Acknowledgments: This study has been supported by U.S. National Science Foundation grant 1438537, American Heart Association Grant-in-Aid 13GRNT17200013, and Tulane University intramural grants. The acoustic tweezing technology is protected by pending patents PCT/US14/55559 and PCT/US2018/014879. Disclosures Khismatullin: Levisonics Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
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Pospisilova, Dagmar, Dusan Holub, Zuzana Zidova, et al. "Erythropoiesis and Iron Metabolism In Diamond-Blackfan Anemia." Blood 122, no. 21 (2013): 2478. http://dx.doi.org/10.1182/blood.v122.21.2478.2478.
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Abstract Diamond-Blackfan anemia (DBA) is a rare congenital red cell aplasia characterized by macrocytic anemia, reticulocytopenia and reduced number of erythroblasts in the bone marrow. Etiology and symptoms of DBA are closely associated with mutations of genes coding for 12 ribosomal proteins. Approximately 40% of patients are dependent on regular transfusions. In chronically transfused DBA patients, severe iron overload with tissue hemosiderosis with the need for iron chelation develops and has a substantial impact on morbidity and mortality of DBA patients. Liver is the most affected organ, but extra-hepatic iron accumulation, although less well documented, appears to occur early and at high frequency. Despite these facts a detailed analysis of iron metabolism in DBA is missing. We therefore aimed to determine selected markers of erythropoid activity and iron metabolism including the levels of the key regulator of iron homeostasis, hepcidin, in 14 DBA patients from the Czech National DBA Registry. Ten patients receive regular transfusions, two are treated with steroids and two are in the remission. None of the patients had signs of an inflammatory process at the time of the examination. Following markers of iron metabolism were analysed: iron, total iron binding capacity, transferrin saturation, ferritin and soluble transferrin receptor (TfR). Serum hepcidin was measured by proteomic analysis. Levels of rowth differentiation factor 15 (GDF 15), aputative marker of erythroid activity, were measured by ELISA. Pearls’ staining was used for the liver iron detection. In all transfusion dependent patients, low levels of soluble TfR and reduced number of erythroblasts in the bone marrow confirm severally suppressed erythropoiesis which corresponded with dramatically elevated serum erythropoietin (EPO) levels. Analysis of iron parameters showed increased transferrin saturation and high ferritin levels. The two patients who are currently in the remission had near normal blood counts and iron parameters. Liver biopsy on 5 selected patients revealed excessive iron accumulation in both liver hepatocytes and macrophages which can be attributed to increased iron uptake and non-effective erythrocytes-derived iron recycling, respectively. Measurement of hepcidin levels showed significant elevation in DBA cohort in comparison with healthy controls (p>0.0005). The highest hepcidin was detected for transfusion dependent patients, the lowest (near normal) for patients in remission. As erythropoiesis is known to produce a signal for hepcidin suppression, patients in remission with restored erythropoietic activity are likely able to attenuate hepcidin expression and increase the pool of iron available for improved erythropoiesis. On the other hand repeated blood transfusions contribute to the suppression of erythropoiesis thus likely relieving hepcidin synthesis and worsening iron recycling. We also found that elevated hepcidin positively correlated with ferritin levels. No correlation was detected with EPO or GDF15, the putative negative regulator of hepcidin production. These results indicate that EPO is an indirect suppressor of hepcidin synthesis and that GDF15 possibly plays a hepcidin-regulatory role in the disease states associated with ineffective erythropoiesis but not in DBA. In conclusion we propose that in DBA patients iron overload develops as a consequence of the combination of repeated transfusions and absent or reduced erythropoiesis in the bone marrow. At the systemic level the increased hepcidin promotes iron retention in macrophages and thus is responsible for impaired iron recycling. Acknowledgments Grant support: Ministry of Health, Czech Republic, grant No. NT11059 to DP and NT/13587 to VD, Czech Grant Agency, grant No. P305/11/1745, and Internal Grant of Palacky University Olomouc (LF_2013_010). We thank dr. Thomas Ganz for validation of our HPLC-MS-based hepcidin measurements. Disclosures: No relevant conflicts of interest to declare.
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Weng, Jianyu, Xin Huang, Xiaomei Chen, et al. "Blocking Stat3 to Regulate the Balance of Th17/Treg in Cgvhd Therapy." Blood 126, no. 23 (2015): 5420. http://dx.doi.org/10.1182/blood.v126.23.5420.5420.
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Abstract Background: Our preliminary research found that STAT3, IL-17A, and IL-21 expressed in cGVHD patients. So, we provide the blocking STAT3 signal to the induction of Treg cells differentiation, and to provide experimental basis on new targets of cGVHD immunotherapy. Methods: 1. Mice spleen CD4+ CD62L+ naiveT cells were separated by immune magnetic bead and then activated for 72 h. After 96 h infection with STAT3-shRNA and negative control lentivirus, the Th subgroup proportion were measured by flow cytometry. Th related cytokines levels test by Luminex. Real time quantitative PCR was to detect STAT3 and Th subgroup related transcription factor mRNA levels. CD117+ mouse bone marrow stem progenitor cells were sorted by flow cytometry, and transfected by STAT3-shRNA. Inhibition of STAT3 gene in mRNA level was measured at 96 h. Cell proliferation activity was test with CCK8 kit, and cell apoptosis rate determined by flow cytometry. Differentiation of CD117+ cells was induced by 2.2% of methyl cellulose and different cytokines. 2. BALB/c female mice, after the linear accelerator 700cGy of whole body irradiation, accepted miHA mismatched male B10. D2 mice bone marrow cells and spleen cells (8 x 106, 1:1). Randomly assigned 6 mice of cGVHD clinical score of 0.6 or above to each group. After STAT3-shRNA or negative control lentivirus treatment, the observe end point was 58th day after transplantation. The clinical and pathologic scores compared. Th17 and Treg cells measured by flow cytometry. Th related cytokines measured by Luminex. Purpose genes in blood and protein expression levels in target organs were found by Q-PCR and western blot test, respectively. Results: 1. The Th17 / Treg ratio of shRNA group was significantly decreased than that in the NC group (P < 0.05). Except for the Foxp3 gene, other purpose genes, including T-bet, Gata3, RORγt, TGFβ, Notch1, and Jagged2 mRNA levelsin interference group were cut. GM-CSF, IFN-gamma, beta, IL- 3, IL-2, IL-4, IL-6, TNF alpha, IL-17, IL-22a, IL-27, and IL-9 factor expression levels were significant difference between shRNA and negative control group (P < 0.05). There was no significant difference of cell proliferation activity, early apoptosis rate, and differentiation ability in STAT3-shRNA treated CD117+ bone marrow, compared with negative control group and blank control group (P > 0.05). 2. After 50th day, shRNA treatment group appear hair recovery, energy recovery, weight gain, shortness of breath better, mean of cGVHD score decreased. At the 58th day, clinical scores of cGVHD between shRNA treatment group and the negative control group overall mean difference was statistically significant (P < 0.05). cGVHD pathological score of lungs in shRNA treat group reduced (P < 0.05). STAT3mRNA levels in peripheral blood, phosphorylated STAT3, and STAT3 expression level of lung declined than control groups. The proportion of Th17 / Treg cells of spleen was significant reduced in shRNA group, compared with negative control group (P < 0.05). Conclusion: 1. STAT3 knocking down in naïve CD4 + Th cells induced the increased Treg cells, and the decreased Th17 cells. IL-2 confirmed to promote the growth of Treg cells. It speculated that blocking STAT3 might bring Th9 cells differentiation. STAT3 blocking in CD117+ stem progenitor cells have no significant effect on the proliferation, apoptosis and differentiation, validation the safety of STAT3-shRNA. 2. STAT3-shRNA treatment cGVHD mice in vivo achieved curative effect. The main target organs was the lung, which might be closely related to the fall in the proportion of Th17 /Treg. STAT3 may be used as a new target for immunotherapy of cGVHD. Acknowledgment The project was sponsored by grants from National Natural Science Foundation of China (No. 30972790; No.81270648; No.81370665; No.81300446), Provincial Natural Science Foundation of Guangdong (No. S2012010009560), Provincial Science and Technology Planning Project of Guangdong (No.2013B021800186; No.2013B021800201), and Science and Technology Planning Project of Guangzhou (No. 201400000003-4, 201400000003-1). Disclosures No relevant conflicts of interest to declare.
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Sharma, Anupama, Abhay Bansal, and Vinay Rishiwal. "SBADR: stable and bandwidth aware dynamic routing protocol for mobile ad hoc network." International Journal of Pervasive Computing and Communications 16, no. 3 (2020): 205–21. http://dx.doi.org/10.1108/ijpcc-05-2019-0043.
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Purpose Quality communication is a big challenge in mobile ad hoc networks because of a restricted environment for mobile devices, bandwidth-constrained radio connections, random mobility of connected devices, etc. High-quality communication through wireless links mainly depends on available bandwidth, link stability, energy of nodes, etc. Many researchers proposed stability and link quality methods to improve these issues, but they still require optimization. This study aims to contribute towards better quality communication in temporarily formed networks. The authors propose the stable and bandwidth aware dynamic routing (SBADR) protocol with the aim to provide an efficient, stable path with sufficient bandwidth and enough energy hold nodes for all types of quality of service (QoS) data communication. Design/methodology/approach The proposal made in this work used received signal strength from the media access control (MAC) layer to estimate the stability of the radio connection. The proposed path stability model combines the stability of the individual link to compute path stability. The amount of bandwidth available for communication at a specific time on a link is defined as the available link bandwidth that is understood as the maximum throughput of that link. Bandwidth as a QoS parameter ensures high-quality communication for every application in such a network. One other improvement, towards quality data transmission, is made by incorporating residual energies of communicating and receiving nodes in the calculation of available link bandwidth. Findings Communication quality in mobile ad hoc network (MANET) does not depend on a single parameter such as bandwidth, energy, path stability, etc. To address and enhance quality communication, this paper focused on high impact factors, such as path stability, available link bandwidth and energy of nodes. The performance of SBADR is evaluated on the network simulator and compared with that of other routing protocols, i.e. route stability based QoS routing (RSQR), route stability based ad-hoc on-demand distance vector (RSAODV) and Ad-hoc on-demand distance vector (AODV). Experimental outcomes show that SBADR significantly enhanced network performance in terms of throughput, packet delivery ratio (PDR) and normalized control overhead (NCO). Performance shows that SBADR is suitable for any application of MANET having random and high mobility. Research limitations/implications QoS in MANET is a challenging task. To achieve high-quality communication, the authors worked on multiple network parameters, i.e. path stability, available link bandwidth and energy of mobile nodes. The performance of the proposed routing protocol named SBADR is evaluated by a network simulator and compared with that of other routing protocols. Statistical analysis done on results proves significant enhancement in network performance. SBADR is suitable for applications of MANET having random and high mobility. It is also efficient for applications having a requirement of high throughput. Practical implications SBADR shows a significant enhancement in received data bytes, which are 1,709, 788 and 326 more in comparison of AODV, RSAODV and RSQR, respectively. PDR increased by 21.27%, 12.1%, 4.15%, and NCO decreased by 9.67%, 5.93%, 2.8% in comparison of AODV, RSAODV and RSQR, respectively. Social implications Outcomes show SBADR will perform better with applications of MANET such as disaster recovery, city tours, university or hospital networks, etc. SBADR is suitable for every application of MANET having random and high mobility. Originality/value This is to certify that the reported work in the paper entitled “SBADR: stable and bandwidth aware dynamic routing protocol for mobile ad hoc network” is an original one and has not been submitted for publication elsewhere. The authors further certify that proper citations to the previously reported work have been given and no data/tables/figures have been quoted verbatim from the other publications without giving due acknowledgment and without permission of the author(s).
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Szczepanek, Joanna, Joanna Laskowska, Agata Labedzka, Jan Styczynski, and Andrzej Tretyn. "Genetic Mechanisms Of Cytarabine, Etoposide and Daunorubicin Resistance In Pediatric Acute Leukemias." Blood 122, no. 21 (2013): 4938. http://dx.doi.org/10.1182/blood.v122.21.4938.4938.
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Abstract Introduction Drug resistance is a major problem in chemotherapy of leukemia. Several mechanisms of this phenomenon have been identified, but the underlying genomic changes are still poorly understood. Lack of drug sensitivity arises from a complex range of molecular events, which ultimately result in the blasts escaping death. Analysis of the gene expression profiles of cancer cells in correlation with in vitro cytotoxicity assay may define mechanisms of sensitivity and resistance to specific drugs. OBJECTIVE: To define and compare whole-genome responses to cytarabine (Ara-C), etoposide (VP16) and daunorubicin (DNR) in pediatric patients diagnosed with acute leukemias, and to explain in vitro chemoresistance phenotype of leukemic blasts. Methods In order to determine the ex vivo drug resistance profile, MTT cytotoxicity assay was performed on mononuclear cells obtained from 51 patients with ALL and 16 patients with AML. Gene expression profiles were prepared on the basis of cRNA hybridization to oligonucleotide arrays of the human genome (Affymetrix). Hierarchical clustering, assignment location and biological function were performed during the correlation analysis for identified probe sets. Verification of the relative expression level of genes (EGR1, GATA2, RUFY3, LDHA, DUSP2, BIN2, ICAM3, TTC28) was carried out by RT-qPCR in the study group and in an independent group of 53 patients. Results Genetic expression profiles were identified, including those appropriate for ALL and AML: 181 and 106 genes for Ara-C, 274 and 314 for VP16, 146 and 495 for the DNR. For each of the drugs, a characteristic group of genes or processes that are responsible for the lack of sensitivity, were identified: (1) for Ara-C: overexpression of genes responsible for removing the drug from the cells, as well as changes in the nucleic acid metabolic process, especially transcription from RNA polymerase II promoter (eg. ZBTB16, FOSB, NFATC1, ZNF518B, PHF20L1 and RUFY); (2) for VP16: changes in expression level of genes involved in the regulation of mRNA transcription and DNA metabolism genes, including those controlling replication as well as those belonging to the double helix damage repair enzymes and genes participating in post-transcriptional mRNA splicing (eg. TOP2B, CSNK1E, BRIP1, ATR, MSH3 and MSH6); (3) for DNR: differentiated expression of factors involved in the replication and transcription processes, increased expression of kinases and intensification of the DNA repair processes (eg. ATF2, GATA2, TOX, RUNX3, MNDA, ST18, TFDP1, NFE2, SOX11 and PAX5). For each profile several common genes, such as: AGAP1, PRKCH, RAB31, BCL2A1, GCA, HLA-DRA, HLA-DPA1, IL8, RGS10, CEBPD, CLEC2, ANXA1, PLEK, S100A8, SLC, CXCL2, SOX, BTG, DEFA4 and TPD52, were identified. Pathway and functional gene ontology analysis showed that several features, independent of the initial type of leukemia cells and pattern of resistance include: overexpression of chemokines and hydrolases, increase in the expression of genes responsible for the maintenance of chromatin architecture, overexpression of anti-apoptotic genes, decrease in expression level of genes that promote apoptosis, decrease in gene expression of Wnt signaling pathway, down regulation of the expression of transcription factors, changes in the expression level of genes associated with the activation of B and T lymphocytes, differences in expression of genes responsible for the cell surface receptor linked signal transduction and intracellular signaling cascade. Conclusions This analysis showed that the mechanism of response to drugs is significantly genetically determined. Predictive sets of marker genes and functional groups for simultaneous assessment of the sensitivity to these 3 drugs, were identified. Many of these changes converge and ultimately lead to avoidance of apoptosis and further over-proliferation of cancer cells. This could also suggest that targeting these pathways as potential pharmacogenetics and therapeutic candidates may be useful for improving treatment outcomes in pediatric acute leukemias. This could also suggest that targeting these pathways as potential pharmacogenetics and therapeutic candidates may be useful for improving treatment outcomes. Acknowledgments: This study was supported by Grant from the National Science Centre No. DEC-2011/03/D/NZ5/05749. Disclosures: No relevant conflicts of interest to declare.
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Shi, Jumei, Yi Tao, Xiaosong Wu, Xiaojing Hu, Yang Shao, and Jun Hou. "Valproic Acid Upregulates NKG2D Ligand Expression and Potentially Enhances Natural Killer Cell–mediated Cytolysis of Myeloma." Blood 118, no. 21 (2011): 5061. http://dx.doi.org/10.1182/blood.v118.21.5061.5061.
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Abstract Abstract 5061 Objective: Multiple myeloma (MM) is a plasma cell malignancy. Although high-dose chemotherapy supported by autologous hematopoietic stem-cell transplantation can produce higher response rates and longer survival than standard chemotherapy, MM remains largely incurable by current therapeutic strategies. Clinical and preclinical data have been demonstrated that natural killer (NK) cells have an anti-myeloma effect. However, low NK cell activity affected the successful utilization of NK cell adoptive immunotherapy for myeloma. In this study, we investigated the effect of valproic acid (VPA), as a histone deacetylase inhibitor, on the expression of NKG2D ligands on human myeloma cell lines and primary myeloma cells derived from patients. We also evaluated the sensitivity of myeloma cells to NK cell-mediated lysis before and after treatment with VPA, and the possible underlying mechanisms. Method: ARK, OPM2 myeloma cell lines and primary myeloma cells (n = 4) from patients with myeloma were cultured with 0.5–3mM VPA for 24 to 72 hours. Cells cultured without VPA were as control groups. To evaluate the effect of VPA on NKG2D ligand expression of myeloma cells, mRNA and protein expression of NKG2D ligands (including MICA/B, ULBP1, ULBP2 and ULBP3) of myeloma cells were tested by Real time-PCR and flow cytometry. 51Cr release assay and NKG2D antibody blocking experiments were combined to examine the susceptibility of myeloma cells to NK cell-mediated lysis in response to VPA and the possible killing mechanisms. Results: ARK and OPM-2 myeloma cell lines were treated with various concentrations of VPA. The most prominent upregulations of mRNA expressions of MICA/B, ULBP2 and ULBP 3 were observed in the two tested myeloma cell lines. The enhancement of cell surface expression of MICA/B, ULBP2 and ULBP 3 was detected by flow cytometry after cells treatment with VPA. We also found that VPA upregulated MICA/B expression on OPM2 MM cell line in a time- and dose-dependent manner. These data suggest that VPA could upregulate expression of NKG2D ligands in myeloma cell line at both the mRNA and protein levels. A similar increase of surface expression of NKG2D ligands was obtained in 2–3 mM VPA treated primary MM cells (n=4). NK cell function was studied by 51Cr release assay. VPA treatment of OPM2 showed higher sensitivity to NK cell lysis than untreated cells (specific killing: 72.8±6.2% vs 32.1±3.7% at E/T 10:1, p <0.01). The killing of VPA treatment of patient myeloma cells by NK cells also significantly increased compared with control cells (specific killing: 46.7±5.6% vs 21.6±4.5% at E/T 10:1, n=4, p <0.01). The enhancing effect of VPA was blocked by pretreatment of OPM2 cells with a combination of anti-MICA/B, anti-ULBP1,2,3 mAbs or pretreatment of NK cells with anti-NKG2D mAbs, indicating the contribution of NKG2D-NKG2D ligands interations to VPA-modulated lysis of myeloma. We also found that constitutive phosphorylated extracellular signal-regulated kinase (ERK) but not AKT signaling pathway may be involved in VPA-induced higher NKG2D ligand expression. Conclusion: Histone deacetylase inhibitor valproic acid could upregulate cell surface expression of NKG2D ligands, rendering myeloma cells more sensitive to NK cells, and thereby enhance NK cell–mediated lysis of myeloma. Our findings imply that regulation of the expression of NKG2D ligands by treatment with histone deacetylase inhibitors may be an attractive strategy for immunotherapy of myeloma. Acknowledgments: This work was supported by grants from National Natural Science Foundation of China (81071856 and 30973450 to JS) and funds from Shanghai Tenth People's Hospital (10RD103 and 11SC103 to JS). Disclosures: No relevant conflicts of interest to declare.
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Papayannidis, Cristina, Viviana Guadagnuolo, Ilaria Iacobucci, et al. "PF-04449913 Reverts Multi Drug Resistance (MDR) by a Strong Down-Regulation of ABCA2 and BCL2 on Leukemia Stem Cells in Phase I Acute Myeloid Leukemia and Chronic Myeloid Leukemia Treated Patients." Blood 118, no. 21 (2011): 1429. http://dx.doi.org/10.1182/blood.v118.21.1429.1429.
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Abstract Abstract 1429 The development of resistance against chemotherapy remains one of the major challenges in the clinical management of leukemia. The Sonic Hedgehog (Hh) pathway is an essential regulator of multidrug resistance (MDR) in leukemia by exerting it's effect on leukaemia stem cells (LSC). PF-04449913 is a selective and potent small molecule inhibitor of the Hh pathway and leukemia self-renewal and is currently being evaluated in Phase I clinical trials. In order to evaluate the activity of PF-0444913 in overcoming the drug resistance of leukemia stem cells, we studied leukemia stem cell population (CD34+ subpopulation) collected before and after 28 days treatment in a phase I dose escalation protocol (Clinical Trial Gov. NTC00953758) enrolling selected hematological malignancies including Myelofibrosis (MF), MDS, Chronic Myeloid Leukemia (CML), Chronic Myelomonocytic leukemia (CMML) and Acute Myeloid Leukemia (AML) patients. We were able to collect and separate highly purified (98%) bone marrow hematopoietic progenitor cells (CD34+ populations) in 5 AML, 1 MF and 2 CML patients, by immunomagnetic separation, and analyze them for gene expression profile (GEP) using Affimetrix HG-U133 Plus 2.0 platform. We have observed that 1197 genes were differentially expressed between CD34+ cells collected before and after 28 days of PF-04449913 dose finding oral therapy. Among these genes, we demonstrated a down regulation of Bcl2 (fold change −1.03004; p value= 0.01), ABCA2 (fold change −1.08966; p value=0.03), Bcl2l13 (fold change −1,04259; p-value=0,027642), Bcl2l2 (fold change −1,17214; p-value=0,000768), Casp4 (fold change −1,06551; p-value=0,032428), Casp7 (fold change −1,01569; p-value=0,006688), Casp10 (fold-change −1,3076; p-value=0,050431), ABCF1 (fold change −1,04999; p-value=0,07213). On the contrary, ABCB1 (fold change 1,46592) and ABCG2 (fold change −1,16103) are respectively up and down regulated, with a not statistically significant p-value (0,35375 and 0,288194 respectively). Bcl2 (B-cell lymphoma 2), Bcl2l2 (Bcl2-like protein 2) and Bcl2l13 (Bcl2-like 13) are the founding members of the Bcl-2 family of apoptosis regulator proteins. Recent studies showed that Hh signals upregulate Bcl2 to promote cellular survival. Casp 4,7,10 (Caspases, or c ysteine-asp artic proteases) are a family of cysteine proteases that play essential roles in apoptosis, necrosis, and inflammation. ABCA2 (ATP-binding cassette sub-family A member 2), ABCF1 (ATP-binding cassette sub-family F member 1), ABCB1 (ATP-binding cassette sub-family B member 1, MDR1), ABCG2 (ATP-binding cassette sub-family G member 2) belong to the superfamily of adenosine triphosphate-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. One mechanism of MDR is the increased expression of ABC drug transporters that mediate energy-dependent transport of drugs out of the cells against a concentration gradient, resulting in low intracellular drug concentrations. This is a common finding in LSC, and represents an important clinical problem for disease eradication. Furthermore, we evaluated Gli1, Gli2 and Smo expression by GEP, comparing data before and after 28 days of treatment with PF-04449913 and, as expected, we observed a down regulation of Gli1 (fold change −1.0775), Smo (fold change −1.07702), and an up regulation of Gli2 (fold change 1.08191). Our results suggest that PF-04449913 is able to revert MRD mechanisms of LSC by a strong down regulation of genes (Bcl-2, Bcl-2l13, Bcl-2l2, ABCA2, and ABCF1), which are critical for chemoresistance in acute and chronic leukemia patients. Therefore, the combination of PF-04449913 with Tyrosine Kinase inhibitors or conventional chemotherapy could represent a valid new therapeutic approach in these haematological malignancies. Acknowledgments. Work supported by Pfizer, European LeukemiaNet, FIRB 2008, PRIN 2009, AIRC, AIL, COFIN, University of Bologna and BolognAIL. Disclosures: Levin: Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Courtney:Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Baccarani:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jamieson:Wintherix: Equity Ownership; Pfizer Oncology: Research Funding; Celgene: Research Funding; Novartis: Honoraria. Cortes:Novartis: Consultancy; Novartis: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. McLachlan:Pfizer: Employment. Van Arsdale:Pfizer: Employment. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria.
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Radosova Muchova, Tereza, Eva Reznickova, Zuzana Somikova, et al. "A Novel Dual Class III/Src Family Tyrosine Kinase Inhibitor Is Highly Active Against FLT3-ITD Leukemia Cells In Vivo." Blood 128, no. 22 (2016): 1569. http://dx.doi.org/10.1182/blood.v128.22.1569.1569.
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Abstract Class III receptor tyrosine kinases (RTK), which include c-fms, c-kit, FMS-like tyrosine kinase receptor-3(FLT3) and platelet-derived growth factor receptor (PDGFR) α/β are expressed on acute myelogenous leukemia (AML) cells from the majority of patients and stimulate survival and proliferation of leukemic blasts. FLT3 activation cooperates, for instance, with oncogenic mixed lineage leukemia (MLL) fusion proteins in MLL-induced transformation. The most common FLT3 activation mutation, internal tandem duplication (ITD), is the most frequently observed molecular defect in AML, and it is associated with early relapses and poor prognosis. FLT3-ITD leads to constitutive, ligand-independent activation of the kinase; this results in FLT3 autophosphorylation and induction of several downstream signaling cascades including Ras/MAPK kinase (MEK)/extracellular signal-regulated kinase (ERK) and STAT5 pathways. FLT3 as well as other class III RTK have been widely accepted as suitable drug targets. Several potent inhibitors have been developed, and some of them, such as quizartinib or crenolanib, have demonstrated promising clinical outcomes. However, resistance to these inhibitors remains a significant clinical problem; therefore, development of novel inhibitors is needed. Also Src family tyrosine kinases (SFK) have been proven as therapeutic targets in multiple cancers including leukemia. Here, we developed and tested a novel series of compounds which revealed dual inhibitory activities against class III RTK and SFK, and tested them in vitro against FLT3- and PDGFRα-mutated leukemic cells and in vivo against FLT3-ITD-positive AML. First, we tested kinase selectivity of the novel compounds. Kinase-inhibitory properties were screened at single concentration of 10 nM in biochemical phosphorylation assays against 300 kinases. The compounds revealed strong and specific inhibitory activity especially against class III RTK and SFK. Then, we have used multiple cell lines harboring various oncogenic kinases to test in vitro growth inhibition potential of the compounds. The most potent newly synthesized inhibitor, designated 3922, showed EC50 values at low nanomolar concentrations against FLT3-ITD-positive cell line MV4-11 and FIP1L1-PDGFRα-positive EOL-1 cells. We also used primary cells derived from mouse bone marrow bearing inducible fusion oncogene MLL-ENL-ER (MEER) adapted to growth in cell culture (Takacova et al, 2012, Cancer Cell 21:517). Prior to drug testing, the MEER cells were grown in cell culture media to induce cytokine addiction either to stem cell factor (SCF) or to ligand of FLT3 (FLT3L). The efficacy of 3922 was 5 times more potent against FLT3L-addicted MEER cells than against SCF-addicted cells suggesting that FLT3 is the main target of 3922. We then compared the effect of 3922 on inhibition of FLT3 phosphorylation (pFLT3-Tyr589/591) with quizartinib (Zarrinkar et al, 2009, Blood 114:2984). Both compounds showed to be very efficient inhibitors of FLT3 phosphorylation at nanomolar concentrations, however, 3922 inhibitory effect had longer durability after drug withdrawal when compared with quizartinib. Finally, we determined the activity of 3922 in vivo. A single-dose of 10 mg/kg of 3922 or quizartinib was administered to the mice with subcutaneously implanted MV4-11 xenograft. Quantitation of pFLT3 revealed that the RTK was inhibited by 95% even after 2 hours administration of 3922 and this inhibition sustained 24 hours, in contrast to elevated pFLT3 24 hours after quizartinib administration (Zarrinkar et al, 2009; Gunawardane et al, 2013, Mol Cancer Ther 12:438). After 2 hours, the pERK1/2 levels were reduced by both inhibitors, however, returned to phosphorylation levels comparable to vehicle treated control in 24 hours after administration. The inhibitory effect was more pronounced on phosphorylation of STAT5. Inhibitor 3922 reduced the pSTAT5 level by more than 95% after 24 hours, slightly more effectively than quizartinib. Induction of apoptosis was assessed by PARP cleavage. Cleaved PARP was significantly elevated by 3922 even after 2 hours of treatment, with a pattern similar to the PARP cleavage induced by quizartinib (Gunawardane et al, 2013). In conclusion, we have developed a novel highly potent tyrosine kinase inhibitor effective against AML in vitro and in vivo. Acknowledgment: Supported by NV15-28951A from Ministry of Health, Czech Republic. Disclosures No relevant conflicts of interest to declare.
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Ferreira, Germano A., Carolina H. Thomé, Priscila Santos Scheucher, et al. "LAT2, a Lipid Raft Protein That Participates in AKT Phosphorylation in Mantle Cell Lymphoma, Is a Target for Perifosine Chemotherapy." Blood 124, no. 21 (2014): 923. http://dx.doi.org/10.1182/blood.v124.21.923.923.
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Abstract Introduction: Lipid rafts are highly ordered membrane domains that are enriched in cholesterol and sphingolipids and provide an environment for signal transduction proteins which control cell survival and cell death. Altered raft assembly has been implicated in cancer progression. Alkylphospholipids (APL) inhibit the AKT pathway and induce apoptosis of malignant cells but not of their normal counterparts when used at the same concentration. LAT2 (Linker for activation of T-cells family member 2) is a lipid raft component which is disrupted by APLs in leukemic cells. In the present study we evaluated the effect of perifosine, an APL with anticancer activity in humans, on the LAT2 and AKT pathways using a Mantle Cell Lymphoma (MCL) cell line (Granta-519 cells) as a model. We selected MCL cells to study because AKT is constitutively phosphorylated in this disease. Methods: We determined whether perifosine induced apoptosis of unmodified Granta-519 cells using flow cytometry, we measured caspase-3 activity with a synthetic peptide and detected cleaved caspases by western blotting. Then, we demonstrated the participation of LAT2 in AKT signaling. We used a stable knockdown of LAT2 (lentiviral sh-RNA). After transduction, Granta-519 cells were selected using 0.5 µg/mL puromycin for 5 days. Stable LAT2 knockdown reduced LAT2 levels by 90% (Figure 1A) and showed impaired AKT phosphorylation in the absence of ligands (Figure 1B). Results: Perifosine treatment induced apoptosis of Granta-519 cells and the effective dose 50% (ED-50) was 20 μM. Apoptosis was triggered after 6 hours of incubation and activation of the extrinsic and intrinsic pathways of apoptosis was demonstrated. Perifosine decreased LAT2 abundance after 3 hours of treatment, also decreasing its presence in lipid rafts, and led to a decrease in AKT phosphorylation and downstream components of AKT signaling. Moreover, perifosine impaired AKT phosphorylation in the presence of stimuli such as CD40L (330 ng/mL) in Granta-519 cells after a few minutes of incubation, resulting in an effect similar to that of the PI3K inhibitor Wortmannin (1 µM). In vivo studies using Granta-519 subcutaneous xenografts in NSG mice revealed that stable knockdown of LAT2 cells showed reduced tumor growth. sh-RNA CT cells (0.75x106) were injected into the right flank of five mice and the same number of sh-RNA LAT2 cells were injected into the left flank of the same animals. After 3 weeks, the tumor weight (mean + SD) was 0.52 ± 0.37 g for sh-RNA LAT2 tumors compared to 1.41 ± 0.19 g for sh-RNA CT tumors (p=0.0065) (Figure 1C and 1D). The LAT2 content of sh-RNA LAT2 cells and AKT phosphorylation were also reduced (Figure 1E and 1F). Conclusions: These results demonstrate that LAT2 is an important protein for supporting constitutive AKT phosphorylation/activation and downstream signaling in MCL and suggest that inhibition of LAT2 by APLs may have therapeutic applications. Acknowledgments: This research was supported by FAPESP, FINEP, and CNPq. C.H.T. received fellowships from FAPESP Proc. No. 13/07675-3. G.A.F. received a fellowship from CNPq Proc. 150126/2014-0. G.A.F. and C.H.T. contributed equally to this work Figure 1 Figure 1. In vivo evaluation of LAT2 stable knockdown cells using the NSG mouse model: (A) LAT2 stable knockdown was obtained from Granta-519 cells via lentiviral transduction of shRNA that targets LAT2. The cell line identified as “B” was used for further studies. (B) AKT activation was suppressed in LAT2 stable knockdown Granta-519 cells. Both cell lines were maintained with or without FBS for 24 hours. (C) Representative picture of the NSG mouse model xenotransplated with Granta-519. Equal amount of cells were injected into the left (sh-RNA LAT2) and right (sh-RNA CT) thigh of the animal. (D) Comparison of tumors weight: sh-RNA CT (1.408 g SD±0.19) and sh-RNA LAT2 (0.523 g SD±0.37). (E) Representative western blotting analysis of tumor cells against LAT2. (F) AKT phosphorylation was evaluated by western blotting (representative of two animals). Disclosures No relevant conflicts of interest to declare.
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Shi, Patricia A., Erika Choi, Julia Nguyen, et al. "Three Months of Human Haptoglobin Treatment Decreases Iron Deposition in the Kidneys of Townes Sickle Mice." Blood 126, no. 23 (2015): 2163. http://dx.doi.org/10.1182/blood.v126.23.2163.2163.
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Abstract Introduction: Haptoglobin (Hp), the scavenger for hemoglobin, and hemopexin (Hx), the scavenger for heme, are depleted in most patients with sickle cell disease due to chronic hemolysis. There is mounting evidence of the crucial role of free hemoglobin and/or free heme in mediating inflammatory and oxidative damage in sickle cell disease, including vaso-occlusion and acute chest syndrome. Purified Hp has been used in Japan for a variety of hemolytic conditions and has been proposed as a potential treatment for sickle cell disease. Although infusions of Hp or Hx have been shown to ameliorate vaso-occlusion, acute lung injury, and heme toxicity in sickle cell mouse models, no prior studies have examined the utility of chronic Hp treatment for amelioration of organ damage. We therefore studied the effect of 3 months of chronic Hp treatment in the Townes sickle mouse model. Methods: Male and female Townes mice (Stock number 013071, The Jackson Laboratory) were used for all experiments, starting at 1 or 3 months of age. SS genotype was confirmed by PCR and HPLC. Organ damage in the spleen, liver, and kidneys as previously described was confirmed. Human Hp solution was a kind gift from Bio Product Laboratory (BPL, Hertfordshire, UK). Hp or equivalent volume PBS control was administered intraperitoneally (IP) in the first cohort of 5 mice and then subcutaneously (SC) in the next two cohorts of 7 and 12 mice on a 48-72 hr dosing schedule of Monday, Wednesday, Friday for a period of 3 months. At the end of 3 months treatment, mice were evaluated by the following studies (with concurrent blinding to treatment group for most studies): plasma Hp (ELISA), plasma heme (QuantiChrom heme assay), urine osmolality (osmometer), urine albumin (ELISA), CBC (Advia 120), WBC differential (Advia 120 and manual count), red blood cell ektacyometry (ektacyometer), organ mass (percent of body weight), and organ histology. Results: Mouse Hp levels in SS Townes mice were confirmed to be markedly low compared to Townes AA mice (mean ± SD: SS 2 ± 1 versus AA 39 ± 4 ug/mL). Dose-finding experiments determined that a dose of 200-400 mg/kg IP or SC in SS mice resulted in a 24 hr peak concentration that was 5-14X supraphysiologic, variably physiologic at 48 hr, and absent or almost absent at 72 hr. Chronic dosing at the 400 mg/kg IP in SA mice showed no CBC or organ toxicity. Three successive cohorts of SS mice were treated with Hp (or equivalent volume of PBS): 200 mg/kg IP in 3-month old mice, 400 mg/kg SC in 3-month old mice, and 400 mg/kg SC in 1-month old mice. At the 400 mg/kg dosing levels, there was a significant decrease in iron deposition in the kidneys of both 4-month and 6-month old mice (treatment started at 1-month and 3 months, respectively) (Table 1). There was also a trend towards decreased liver infarction in 6-month old mice (Table 2). Discussion: Functional binding of the administered human Hp to the human Hb of the Townes mice likely occurred, as evidenced by the decrease in iron deposition in the kidneys, suggesting that formation of the complex prevents filtration of Hb into the kidneys. Surprisingly, kidney function as measured by urine osmolality or albumin excretion was not improved, which may be explained by continued heme-laden red cell microparticle filtration (Camus SM, Blood 2015). Encouragingly, however, a trend towards decreased liver infarction in older mice was observed. The less-than-expected effect of Hp on mouse disease severity may also be explained by: 1) continuous physiologic Hp concentrations not being maintained with the dosing frequency while continued hemolysis releases Hb every minute of the day, and 2) CD163-mediated uptake in mice seems to only account for a part of the Hb clearance as opposed to in humans (Etzerodt A, Antioxid Redox Signal 2013). Despite the limitations of the SCD mouse model, the current study suggests haptogobin infusions could be beneficial in SCD patients. Acknowledgment: The authors are grateful to Sandra Suzuka for performing the HPLC. Table 1. Table 1. Kidney iron deposition (scale 1-10) Treatment group 6-month old SS 4-month old SS 400 mg/kg Hp 4.0 ± 1.4 1 ± 1.1 PBS 9.3 ± 0.6 5 ± 2.9 p-value 0.002 0.02 Table 2. Liver infarction (scale 1-10) Treatment group 6-month old SS 4-month old SS 400 mg/kg Hp 2.6 ± 2.0 3.7 ± 2.8 PBS 6.3 ± 2.4 3.8 ± 2.3 p-value 0.07 0.91 Disclosures Belcher: Biogen Idec: Research Funding; Seattle Genetics: Research Funding; CSL Behring: Research Funding. Vercellotti:CSL Behring: Research Funding; Seattle Genetics: Research Funding; Cydan: Research Funding; Biogen Idec: Research Funding.
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Terragna, Carolina, Marina Martello, Mauro Procacci, et al. "An Amplicon-Targeted Ultra-Deep Sequencing Approach Reveals the Presence at the Onset of Multiple Myeloma and the Selection over Time of TP53 Sub-Clonal Variants, Which Adversely Influence Patients' Overall Survival." Blood 126, no. 23 (2015): 24. http://dx.doi.org/10.1182/blood.v126.23.24.24.
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Abstract INTRODUCTION In newly diagnosed Multiple Myeloma (MM) patients (pts), Copy Number (CN) losses of chromosome 17p13, carrying the TP53 tumor-suppressor gene, are strong predictors of poor outcomes. On the contrary, the prognostic relevance of TP53 mutations at the onset of the disease is less clear, due to the very limited frequency of clonal lesions, as revealed by Sanger sequencing. To address this poorly investigated issue, we used an ultra-deep sequencing (UDS) approach to characterize the TP53 structural architecture in both newly diagnosed and relapsed MM pts and to assess the prognostic role and evolution over time of small TP53 mutated sub-clones. SAMPLES AND METHODS A cohort of 99 newly diagnosed MM pts treated up-front with bortezomib-based regimens and autologous stem cell transplantation, was included in this molecular study. In 29 cases, samples were collected both at diagnosis and at relapse(s). DNA was obtained from CD138+ highly purified plasma cells. TP53 gene mutational status was analysed by using an amplicon-targeted UDS approach (GSJ, 454 Roche Life Sciences). In order to discriminate between low frequency sub-clonal TP53 variants and sequencing errors, sequencing raw data were filtered according to cut-off values based on different ranges of sequences' coverage depth. Additional filters were also applied, based on both quality and biological cut-offs, to obtain a final confident list of variants. Analysis of CN alterations (CNAs) was performed by SNPs array and results analysed with ChAS software. RESULTS With a median coverage of 1386X, a list of 129 correctly called TP53 variants (either missense, or nonsense or splice ones), including 20 INDELs, was detected. Only deleterious and N/A variants (according to SIFT classification) were included in the list. Most newly diagnosed MM pts (55%) carried at least one TP53 sub-clonal variant (on average 1.08 variants per pts), with 45/99 (45%) carrying non-mutated TP53. Pts carrying TP53 sub-clonal variants bared also TP53 CN hemizygous losses (20%), CKS1B gains (56%) and cdkn2c losses (14%). According to TP53 sub-clonal mutational load, pts were stratified in two sub-groups, including 28 pts with ≥2 (high load) and 71 with <2 variants (low load), respectively. Eleven out of 129 variants were recurrent (RVs), as being detected in at least 3% of pts, with Variants Allele Frequencies (VAFs) ranging from 0.24 to 70.1% (median 0,53%); RVs were observed in 29 pts. The clinical impact of the TP53 sub-clonal mutational load, as well as of variants recurrence, was evaluated in 90/99 MM (median follow up = 70 months). Results of statistical analysis are summarized in Table 1. Pts carrying either high TP53 sub-clonal mutational load or RVs had significantly shorter OS and OS after relapse, as compared to the others, while no difference between these two groups was seen regarding PFS and TTP. Multivariate analysis showed that high TP53 mutational load, as well as the presence of TP53 RVs, both resulted independent factors adversely affecting OS and OS after relapse (Table 2). Of note, none of the detected genomic aberrations significantly influenced the response to front-line induction therapy. The distribution of both TP53 sub-clonal variants and genomic CNAs was overall modified in samples collected at relapse(s): 90% of relapsed pts carried at least one sub-clonal variant (on average 1.63 variants per pts) with 3/29 (10%) relapsed MM carrying non-mutated TP53. Moreover, 5 different sub-clonal lesions proved a linear increment of both TP53 VAFs (from 29.4% to 54.6%; from 7.8% to 12.4%; from 0.5% to 4.3%) and TP53 CN loss smooth signal (from 7% to 89% and from 50% to 100%), as evaluated in longitudinally collected samples. CONCLUSIONS The UDS analysis of TP53 coding sequence in newly diagnosed MM highlighted for the first time a high rate of variants, recurring with a wide range of frequencies among samples. The increased number of TP53 sub-clonal variants per pts in samples collected at relapse(s), compared to that seen at the onset of the disease, suggests a sub-clonal dynamics over time. This finding might explain the adverse impact of high TP53 sub-clonal mutational load and TP53 RVs on OS, due to a shorter OS after relapse. Acknowledgments: Roche Diagnostics for applicationsupport in the realization of this project. Disclosures Zamagni: Celgene Corporation: Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Ariad: Consultancy; AMGEN: Consultancy; ROCHE: Consultancy; Pfizer: Consultancy; MSD: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria.
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Schroeder, Bradford L., Nicholas W. Fraulini, Matthew D. Marraffino, Wendi L. Van Buskirk, and Cheryl I. Johnson. "Individual Differences in Adaptive Training: Distress, Workload, and Coping with Changes in Difficulty." Proceedings of the Human Factors and Ergonomics Society Annual Meeting 63, no. 1 (2019): 2154–55. http://dx.doi.org/10.1177/1071181319631033.
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Introduction Although one-on-one tutoring offers many benefits in terms of flexibility and engagement, it can prove to be a resource-intensive method of instruction. Adaptive training (AT) is a viable alternative when one-on-one tutoring is impractical. AT caters instructional content based on an individual’s aptitudes, learning styles, preferences, or task performance (Landsberg, Van Buskirk, Astwood, Mercado, & Aakre, 2011). The present study describes an experiment performed to examine the effects of different rates of difficulty adaptation to train an audio-visual change detection task. Previous research has shown that difficulty adaptation has benefits for learning (e.g., Landsberg, Mercado, Van Buskirk, Lineberry, & Steinhauser, 2012; Wickens, Hutchins, Carolan, & Cummings, 2013). However, this may not be universally true. Specifically, people who cope with task difficulty using emotion-focused coping (EFC) may exhibit performance decrements when experiencing changes in difficulty. EFC is a method of dealing with tasks or problems involving self-criticism, self-doubt, and worry (Matthews & Campbell, 1998). EFC is also associated with high levels of task distress (Matthews et al., 2006), and previous research has identified that shifts in task workload can impair subsequent performance and increase distress (e.g., Cox-Fuenzalida, 2007; Helton, Shaw, Warm, Matthews, & Hancock, 2008). This presents a problem, as the difficulty adaptations (and their concomitant shifts in workload) that should improve learning gains may be problematic for those who use EFC. Method The present experiment examined the hypothesis that those who use EFC strategies in stressful situations struggle with task performance when experiencing changes in task demands. Ninety-five volunteers completed training in which scenario difficulty adapted based on participant performance. Participants completed five 10-minute scenarios of an audio-visual change detection task. In this task, participants observed and listened to a simulated electronic warfare environment consisting of multiple emitters with unique parameters. These emitters could engage or disengage their signals at any time. Participants were required to submit reports to classify these emitters and indicate when they engaged or disengaged from the environment. They were assigned randomly to one of three groups: within-scenario adaptive where task difficulty changed in real time, between-scenario adaptive where task difficulty changed between scenarios, and a non-adaptive control condition where task difficulty was held constant across scenarios. Data on participants’ pre-training dispositional coping styles were collected using Matthews and Campbell’s (1998) Coping Inventory for Task Stressors (CITS). Additionally, we measured participants’ post-task situational coping styles (CITS), workload (NASA Task Load Index, Hart & Staveland, 1988), and distress (Dundee Stress-States Questionnaire; Matthews et al., 2002) after each of the five scenarios. Results Results indicated no group differences in performance (combined accuracy and timeliness of reports; scored out of 100%), post-task distress, and post-task workload in any of the conditions; however, conditional differences emerged when assessing EFC. We performed a moderated mediation analysis to examine conditional indirect effects of EFC on score, post-task workload, and distress. In this model, dispositional (pre-task) EFC was the predictor variable, situational (post-task) EFC was the mediating variable, and this relationship was moderated by the training condition. The outcome variables were score, post-task distress, and post-task workload. This analysis was performed on all five scenarios, and revealed significant indirect effects for those high in dispositional EFC, such that their performance was worst and their distress and workload were highest in the within-adaptive condition. In the between-adaptive and control conditions, these effects were present in the first scenario but diminished over time. In essence, real-time difficulty adaptation that is too frequent can lead to poor training outcomes for those high in EFC. Discussion These effects are consistent with those of Cox-Fuenzalida (2007) and Helton and colleagues (2008) who suggested that variable shifts in workload could be detrimental to performance. Our results suggest that those who tend to use EFC also tend to struggle with frequent changes in task difficulty. For training purposes, EFC may be an important variable for adaptation prior to training (i.e., macro-adaptation; Park & Lee, 2003). If an adaptive training system offers multiple schedules of difficulty adaptation frequency, one could assign higher-EFC trainees to a less-frequent difficulty adaptation schedule to minimize the risk of lower performance and increased distress and workload. On a similar note, it may also be beneficial to take periodic measurements of trainees’ situational EFC to shift their adaptation schedule to one that is less frequent. In both cases, these approaches to adaptive training would mitigate the negative training outcomes of frequent difficulty adaptation associated with high EFC. Future research should continue to study how trainee individual differences influence the effectiveness of AT. Acknowledgments We gratefully acknowledge Dr. Kip Krebs and the Office of Naval Research who sponsored this work (Funding Doc# N0001417WX00200). We would also like to thank Mr. Derek Tolley for his development of the experimental task. Presentation of this material does not constitute or imply its endorsement, recommendation, or favoring by the U.S. Navy or Department of Defense (DoD). The opinions of the authors expressed herein do not necessarily state or reflect those of the U.S. Navy or DoD. NAWCTSD Public Release 19-ORL045 Distribution Statement A – Approved for public release; distribution is unlimited.
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Sehn, Laurie H., Marek Trněný, Kamal Bouabdallah, et al. "Sustained Overall Survival Benefit of Obinutuzumab Plus Bendamustine Followed By Obinutuzumab Maintenance Compared with Bendamustine Alone in Patients with Rituximab-Refractory Indolent Non-Hodgkin Lymphoma: Final Results of the Gadolin Study." Blood 134, Supplement_1 (2019): 2822. http://dx.doi.org/10.1182/blood-2019-123422.
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Introduction: For patients (pts) with relapsed indolent non-Hodgkin lymphoma (iNHL) who develop resistance to rituximab, treatment options are limited and the prognosis is poor. The open-label, randomized, Phase III GADOLIN (NCT01059630) study compared the efficacy and safety of obinutuzumab (GA101; G) plus bendamustine (B) induction, followed by G maintenance (G-B arm), with B induction (B arm; standard of care) in rituximab-refractory iNHL. The primary analysis in 396 pts (data cutoff: September 1, 2014; median observation time, 21.0 months) showed that Independent Review Committee (IRC)-assessed progression-free survival (PFS; primary endpoint) was significantly longer with G-B (median not reached [NR]) vs B (14.9 months), corresponding to a 45% reduction in risk of progression or death (hazard ratio [HR], 0.55; 95% confidence interval [CI]: 0.40, 0.74; p=0.0001; Sehn et al. Lancet Oncol 2016). The safety profile of G-B was manageable. Here, we report the final analysis of efficacy and safety for GADOLIN (when safety follow-up for all pts had been completed [2 years' safety follow-up from last dose]; data cutoff: November 30, 2018). Methods: Enrolled pts were aged ≥18 years with documented rituximab-refractory iNHL and an ECOG performance status of 0-2. Pts received either G 1000mg intravenously (i.v.) (Days [D] 1, 8, and 15 of Cycle [C] 1, and D1 of C2-6) plus B 90mg/m2/day i.v. (D1 and 2 of C1-6) or B monotherapy (120mg/m2/day i.v., D1 and 2 of C1-6) in 28-day cycles. Following induction, pts in the G-B arm without evidence of progression received G maintenance (1000mg i.v. every 2 months for 2 years or until disease progression). Final analysis endpoints included investigator (INV)-assessed PFS, overall survival (OS), time to new anti-lymphoma treatment (TTNT), and safety. The safety population included pts who received ≥1 dose of study treatment, excluding two pts crossing over to G-B during maintenance. Results: Of 413 iNHL pts in the ITT population (G-B, 204; B, 209), 335 (G-B, 164; B, 171) had follicular lymphoma (FL). Median (range) observation time was 57.5 (0.4-97.6) months for the G-B arm and 47.9 (0-100.9) months for the B arm (i.e. 27.6 and 35.6 months additional follow-up since the primary analysis). Median INV-assessed PFS was 25.8 months for the G-B arm vs 14.1 months for the B arm (HR, 0.57; 95% CI: 0.45, 0.73; p<0.0001) in all iNHL pts (Figure 1A). Overall, fewer iNHL pts died in the G-B (84/204; 41.2%) than in the B (100/203; 49.3%) arm; median OS was 88.3 vs 65.6 months (HR, 0.77; 95% CI: 0.57, 1.03; p=0.0810; 23% risk reduction [Figure 1A]). Median TTNT was also longer with G-B vs B (38.2 vs 18.9 months, respectively [HR, 0.60; 95% CI: 0.47, 0.76]). Results for FL pts were as follows: median PFS, 24.1 vs 13.7 months (HR, 0.51; 95% CI: 0.39, 0.67; p<0.0001 [Figure 1B]); median OS, NR vs 60.3 months (HR, 0.71; 95% CI: 0.51, 0.98; p=0.0343); median TTNT, 33.6 vs 18.0 months (HR, 0.56; 95% CI: 0.43, 0.73). In the safety population (N=407; G-B, 204; B, 203), 149/204 (73.0%) of pts in the G-B arm and 134/203 (66.0%) in the B arm experienced grade ≥3 adverse events (AEs). Compared with B, grade ≥3 neutropenia (37.3% vs 30.0%) and grade ≥3 infusion-related reactions (11.3% vs 5.4%) were more frequent with G-B, and grade ≥3 thrombocytopenia (10.8% vs 15.8%) and anemia (7.4% vs 10.8%) were less frequent. The incidences of grade ≥3 infections (22.5% vs 19.2%) and grade ≥3 second malignancies (7.8% vs 5.9%) were similar between arms. The proportion of pts with serious AEs was 91/204 (44.6%) in the G-B arm and 76/203 (37.4%) in the B arm; fatal AEs were reported in 20/204 (9.8%) and 15/203 (7.4%) of pts, respectively. The most frequent AEs leading to death in the G-B vs B arms were infections (six vs seven pts, respectively) and second malignancies (eight vs four pts, respectively). Safety results in FL pts were comparable with all iNHL pts. Conclusions: Final analysis of the GADOLIN study showed that G-B was associated with a 43% reduction in the risk of progression or death compared with B in pts with rituximab-refractory iNHL and a 49% reduction in pts with FL, with a sustained and clinically relevant OS benefit in pts with FL. There were no new safety signals with longer follow-up. Acknowledgments: The GADOLIN study was sponsored by F. Hoffmann-La Roche Ltd. Third party medical writing assistance, under the direction of Laurie Sehn, was provided by Louise Profit of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd. Disclosures Sehn: TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Trněný:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy; Gilead Sciences: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria. Bouabdallah:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dueck:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Roche: Research Funding. Gribben:Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Lugtenburg:Celgene: Honoraria; Janssen-Cilag: Honoraria; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Genmab: Honoraria. Salles:Epizyme: Consultancy, Honoraria; BMS: Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Knapp:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Liu:Roche Pharma Development, Shanghai, China: Employment. Cheson:Seattle Genetics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding.