Статті в журналах: "MCRYM"

1

Yagita, Kazuhiro, Shun Yamaguchi, Filippo Tamanini, Gijsbertus T. J. van der Horst, Jan H. J. Hoeijmakers, Akira Yasui, Jennifer J. Loros, Jay C. Dunlap, and Hitoshi Okamura. "Dimerization and nuclear entry of mPER proteins in mammalian cells." Genes & Development 14, no. 11 (June 1, 2000): 1353–63. http://dx.doi.org/10.1101/gad.14.11.1353.

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Nuclear entry of circadian oscillatory gene products is a key step for the generation of a 24-hr cycle of the biological clock. We have examined nuclear import of clock proteins of the mammalianperiod gene family and the effect of serum shock, which induces a synchronous clock in cultured cells. Previously, mCRY1 and mCRY2 have been found to complex with PER proteins leading to nuclear import. Here we report that nuclear translocation of mPER1 and mPER2 (1) involves physical interactions with mPER3, (2) is accelerated by serum treatment, and (3) still occurs in mCry1/mCry2double-deficient cells lacking a functional biological clock. Moreover, nuclear localization of endogenous mPER1 was observed in culturedmCry1/mCry2 double-deficient cells as well as in the liver and the suprachiasmatic nuclei (SCN) ofmCry1/mCry2 double-mutant mice. This indicates that nuclear translocation of at least mPER1 also can occur under physiological conditions (i.e., in the intact mouse) in the absence of any CRY protein. The mPER3 amino acid sequence predicts the presence of a cytoplasmic localization domain (CLD) and a nuclear localization signal (NLS). Deletion analysis suggests that the interplay of the CLD and NLS proposed to regulate nuclear entry of PER in Drosophilais conserved in mammals, but with the novel twist that mPER3 can act as the dimerizing partner.

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2

Sanada, Kamon, Yuko Harada, Mihoko Sakai, Takeshi Todo, and Yoshitaka Fukada. "Serine phosphorylation of mCRY1 and mCRY2 by mitogen-activated protein kinase." Genes to Cells 9, no. 8 (August 2004): 697–708. http://dx.doi.org/10.1111/j.1356-9597.2004.00758.x.

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3

Kume, Kazuhiko, Mark J. Zylka, Sathyanarayanan Sriram, Lauren P. Shearman, David R. Weaver, Xiaowei Jin, Elizabeth S. Maywood, Michael H. Hastings, and Steven M. Reppert. "mCRY1 and mCRY2 Are Essential Components of the Negative Limb of the Circadian Clock Feedback Loop." Cell 98, no. 2 (July 1999): 193–205. http://dx.doi.org/10.1016/s0092-8674(00)81014-4.

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4

Lee, Kyung-Ha, Sung-Hoon Kim, Hwa-Rim Lee, Wanil Kim, Do-Yeon Kim, Jae-Cheon Shin, Seung-Hee Yoo, and Kyong-Tai Kim. "MicroRNA-185 oscillation controls circadian amplitude of mouse Cryptochrome 1 via translational regulation." Molecular Biology of the Cell 24, no. 14 (July 15, 2013): 2248–55. http://dx.doi.org/10.1091/mbc.e12-12-0849.

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Mammalian circadian rhythm is observed not only at the suprachiasmatic nucleus, a master pacemaker, but also throughout the peripheral tissues. Investigation of the regulation of clock gene expression has mainly focused on transcriptional and posttranslational modifications, and little is known about the posttranscriptional regulation of these genes. In the present study, we investigate the role of microRNAs (miRNAs) in the posttranscriptional regulation of the 3′-untranslated region (UTR) of the mouse Cryptochrome 1 (mCry1) gene. Knockdown of Drosha, Dicer, or Argonaute2 increased mCry1-3′UTR reporter activity. The presence of the miRNA recognition element of mCry1 that is important for miR-185 binding decreased mCRY1 protein, but not mRNA, level. Cytoplasmic miR-185 levels were nearly antiphase to mCRY1 protein levels. Furthermore, miR-185 knockdown elevated the amplitude of mCRY1 protein oscillation. Our results suggest that miR-185 plays a role in the fine-tuned regulation of mCRY1 protein expression by controlling the rhythmicity of mCry1 mRNA translation.

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5

Woo, Kyung-Chul, Dae-Cheong Ha, Kyung-Ha Lee, Do-Yeon Kim, Tae-Don Kim, and Kyong-Tai Kim. "Circadian Amplitude of Cryptochrome 1 Is Modulated by mRNA Stability Regulation via Cytoplasmic hnRNP D Oscillation." Molecular and Cellular Biology 30, no. 1 (October 26, 2009): 197–205. http://dx.doi.org/10.1128/mcb.01154-09.

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ABSTRACT The mammalian circadian rhythm is observed not only at the suprachiasmatic nucleus, a master pacemaker, but also throughout the peripheral tissues. Its conserved molecular basis has been thought to consist of intracellular transcriptional feedback loops of key clock genes. However, little is known about posttranscriptional regulation of these genes. In the present study, we investigated the role of the 3′-untranslated region (3′UTR) of the mouse cryptochrome 1 (mcry1) gene at the posttranscriptional level. Mature mcry1 mRNA has a 610-nucleotide 3′UTR and mediates its own degradation. The middle part of the 3′UTR contains a destabilizing cis-acting element. The deletion of this element led to a dramatic increase in mRNA stability, and heterogeneous nuclear ribonucleoprotein D (hnRNP D) was identified as an RNA binding protein responsible for this effect. Cytoplasmic hnRNP D levels displayed a pattern that was reciprocal to the mcry1 oscillation. Knockdown of hnRNP D stabilized mcry1 mRNA and resulted in enhancement of the oscillation amplitude and a slight delay of the phase. Our results suggest that hnRNP D plays a role as a fine regulator contributing to the mcry1 mRNA turnover rate and the modulation of circadian rhythm.

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6

Rodriguez, Michael, and Kevin Trainor. "A conceptual model of the drivers and outcomes of mobile CRM application adoption." Journal of Research in Interactive Marketing 10, no. 1 (March 14, 2016): 67–84. http://dx.doi.org/10.1108/jrim-12-2014-0075.

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Purpose – Many organizations still struggle with sales force technology implementation because of low user adoption rates. The ubiquity of mobile computing devices, such as smartphones and tablets, and the proliferation of mobile customer relationship management (mCRM) applications, may lead to increased CRM adoption and higher returns on CRM technology investments. The purpose of this study is to attempt to extend the current literature by developing a model of mCRM antecedents and outcomes by incorporating the idiosyncratic mCRM characteristics that have not yet been examined in the sales technology literature. Design/methodology/approach – This research utilizes the technology acceptance model and the technology-to-performance chain as the foundation of a conceptual model of the drivers and outcomes of mCRM adoption. Findings – This conceptual study provides several contributions to both the sales technology literature and to practitioners within sales organizations. The proposed conceptual model outlines the benefits of providing mCRM capabilities to sales professionals. These benefits include increased productivity, sales activity and collaboration among both internal stakeholders (management and peers) and external stakeholders (prospects and customers). Originality/value – Despite the increased use of mobile applications in sales, research on this particular form of technology is limited, and sales researchers have yet to examine mCRM or its relationship to sales performance. Therefore, the purpose of this research is to forward a conceptual model that allows researchers to explore the drivers of mCRM use and how mCRM influences individual and organizational-level outcomes.

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7

Chaves, Inês, Kazuhiro Yagita, Sander Barnhoorn, Hitoshi Okamura, Gijsbertus T. J. van der Horst, and Filippo Tamanini. "Functional Evolution of the Photolyase/Cryptochrome Protein Family: Importance of the C Terminus of Mammalian CRY1 for Circadian Core Oscillator Performance." Molecular and Cellular Biology 26, no. 5 (March 1, 2006): 1743–53. http://dx.doi.org/10.1128/mcb.26.5.1743-1753.2006.

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ABSTRACT Cryptochromes (CRYs) are composed of a core domain with structural similarity to photolyase and a distinguishing C-terminal extension. While plant and fly CRYs act as circadian photoreceptors, using the C terminus for light signaling, mammalian CRY1 and CRY2 are integral components of the circadian oscillator. However, the function of their C terminus remains to be resolved. Here, we show that the C-terminal extension of mCRY1 harbors a nuclear localization signal and a putative coiled-coil domain that drive nuclear localization via two independent mechanisms and shift the equilibrium of shuttling mammalian CRY1 (mCRY1)/mammalian PER2 (mPER2) complexes towards the nucleus. Importantly, deletion of the complete C terminus prevents mCRY1 from repressing CLOCK/BMAL1-mediated transcription, whereas a plant photolyase gains this key clock function upon fusion to the last 100 amino acids of the mCRY1 core and its C terminus. Thus, the acquirement of different (species-specific) C termini during evolution not only functionally separated cryptochromes from photolyase but also caused diversity within the cryptochrome family.

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8

Fang, Liping, Linyan Huang, Gang Yang, Yang Jiang, Haiping Liu, Bingwen Lu, Yaxian Zhao, and Wen Tian. "Development of a Water Matrix Certified Reference Material for Volatile Organic Compounds Analysis in Water." Molecules 26, no. 14 (July 20, 2021): 4370. http://dx.doi.org/10.3390/molecules26144370.

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Water matrix certified reference material (MCRM) of volatile organic compounds (VOCs) is used to provide quality assurance and quality control (QA/QC) during the analysis of VOCs in water. In this research, a water MCRM of 28 VOCs was developed using a “reconstitution” approach by adding VOCs spiking, methanol solution into pure water immediately prior to analysis. The VOCs spiking solution was prepared gravimetrically by dividing 28 VOCs into seven groups, then based on ISO Guide 35, using gas chromatography-mass spectrometry (GC-MS) to investigate the homogeneity and long-term stability. The studies of homogeneity and long-term stability indicated that the batch of VOCs spiking solution was homogeneous and stable at room temperature for at least 15 months. Moreover, the water MCRM of 28 VOCs was certified by a network of nine competent laboratories, and the certified values and expanded uncertainties of 28 VOCs ranged from 6.2 to 17 μg/L and 0.5 to 5.3 μg/L, respectively.

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9

Mrosovsky, N. "FURTHER CHARACTERIZATION OF THE PHENOTYPE OFmCry1/mCry2-DEFICIENT MICE." Chronobiology International 18, no. 4 (January 2001): 613–25. http://dx.doi.org/10.1081/cbi-100106076.

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10

Jimeno, A., P. Kulesza, G. Cusatis, A. Howard, Y. Khan, W. Messersmith, D. Laheru, E. Garrett-Mayer, S. D. Baker, and M. Hidalgo. "Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 3020. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3020.

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3020 Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner. No significant financial relationships to disclose.

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11

Ranjan, Jayanthi, and Vishal Bhatnagar. "A holistic framework for mCRM – data mining perspective." Information Management & Computer Security 17, no. 2 (June 5, 2009): 151–65. http://dx.doi.org/10.1108/09685220910964018.

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12

Griffioen, Jaco, Monique van der Drift, and Hans van den Broek. "Enhancing Maritime Crew Resource Management Training by Applying Resilience Engineering: A Case Study of the Bachelor Maritime Officer Training Programme in Rotterdam." Education Sciences 11, no. 8 (July 23, 2021): 378. http://dx.doi.org/10.3390/educsci11080378.

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This paper sets out to enhance current Maritime Crew Resource Management (MCRM) training, and with that to improve the training of technical and non-technical skills given to bachelor maritime officers. The rationale for CRM training is improving safety performance by reducing accidents caused by human error. The central notion of CRM training is that applying good resource management principles during day-to-day operations will lead to a beneficial change in attitudes and behaviour regarding safety. This article therefore indicates that enhanced MCRM should play a more structural role in the training of student officers. However, the key question is: what are the required changes in attitude and behaviour that will create sufficient adaptability to improve safety performance? To provide an answer, we introduce the Resilience Engineering (RE) theory. From an RE point of view, we elaborate on the relation between team adaptability and safety performance, operationalized as a competence profile. In addition, a case study of the ‘Rotterdam Approach’ will be presented, in which the MCRM training design has been enhanced with RE, with the objective to train team adaptability skills for improved safety performance.

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13

Oster, H. "Disruption of mCry2 restores circadian rhythmicity in mPer2 mutant mice." Genes & Development 16, no. 20 (October 15, 2002): 2633–38. http://dx.doi.org/10.1101/gad.233702.

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14

Oster, H. "Loss of circadian rhythmicity in aging mPer1-/-mCry2-/- mutant mice." Genes & Development 17, >11 (June 1, 2003): 1366–79. http://dx.doi.org/10.1101/gad.256103.

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15

Jimeno, Antonio, Michelle A. Rudek, Peter Kulesza, Wen Wee Ma, Jenna Wheelhouse, Anna Howard, Yasmin Khan, et al. "Pharmacodynamic-Guided Modified Continuous Reassessment Method–Based, Dose-Finding Study of Rapamycin in Adult Patients With Solid Tumors." Journal of Clinical Oncology 26, no. 25 (September 1, 2008): 4172–79. http://dx.doi.org/10.1200/jco.2008.16.2347.

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Purpose Pharmacodynamic studies are frequently incorporated into phase I trials, but it is uncommon that they guide dose selection. We conducted a dose selection study with daily rapamycin (sirolimus) in patients with solid tumors employing a modified continuous reassessment method (mCRM) using real-time pharmacodynamic data as primary dose-estimation parameter. Patients and Methods We adapted the mCRM logit function from its classic toxicity-based input data to a pharmacodynamic-based input. The pharmacodynamic end point was skin phospho-P70 change after 28 days. Pharmacodynamic effect was defined as at least 80% inhibition from baseline. The first two dose levels (2 and 3 mg) were evaluated before implementing the mCRM, and the data used to estimate the next dose level based on statistical modeling. Toxicity-based boundaries limited the escalation steps. Other correlates analyzed were positron emission tomography (PET) and computed tomography, pharmacokinetics, phospho-P70 in peripheral-blood mononuclear cells, and tumor biopsies in patients at the maximum-tolerated dose (MTD). Results Twenty-one patients were enrolled at doses between 2 and 9 mg. Pharmacodynamic effect occurred across dose levels, and toxicity boundaries ultimately drove dose selection. The MTD of daily oral rapamycin was 6 mg. Toxicities in at least 20% were hyperglycemia, hyperlipidemia, elevated transaminases, anemia, leucopenia, neutropenia, and mucositis. Pharmacokinetics were consistent with prior data, and exposure increased with dose. No objective responses occurred, but five previously progressing patients received at least 12 cycles. PET showed generalized stable or decreased glucose uptake unrelated to antitumor effect. Conclusion mCRM-based dose escalation using real-time pharmacodynamic assessment was feasible. However, the selected pharmacodynamic end point did not correlate with dose. Toxicity ultimately drove dose selection. Rapamycin is a well-tolerated and active oral anticancer agent.

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16

Kingsmore, S. F., D. P. Vik, C. B. Kurtz, P. Leroy, B. F. Tack, J. H. Weis, and M. F. Seldin. "Genetic organization of complement receptor-related genes in the mouse." Journal of Experimental Medicine 169, no. 4 (April 1, 1989): 1479–84. http://dx.doi.org/10.1084/jem.169.4.1479.

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Using an interspecific cross, gene linkage relationships among members of the murine complement receptor-related genes, C4bp, Cfh, Mcry, and Mcr2, were analyzed by segregation of RFLP in 200 mice. The human homologues of these genes are tightly linked, composing the RCA locus, which maps to human chromosome (Chr.)1q32, within a large linkage group conserved between human Chr.1q21-32 and mouse Chr.1. RFLP associated with C4bp and Cfh map within this conserved linkage group; Cfh is located 9 cM telomeric to C4bp, which is consistent with linkage data for their human homologues. Mcry and Mcr2, while tightly linked, are located outside the conserved group, 40 cM telomeric to C4bp. These data suggest that a translocation or inversion occurred within the RCA family during the evolution of the mouse, defining a breakpoint of this large conserved linkage group.

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17

Zheng, Vanessa. "The value proposition of adopting mCRM strategy in UK SMEs." Journal of Systems and Information Technology 13, no. 2 (May 3, 2011): 223–45. http://dx.doi.org/10.1108/13287261111136025.

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18

Ji, Yaoting, Yue Qin, Hongbing Shu, and Xiaodong Li. "Methylation analyses on promoters of mPer1, mPer2, and mCry1 during perinatal development." Biochemical and Biophysical Research Communications 391, no. 4 (January 2010): 1742–47. http://dx.doi.org/10.1016/j.bbrc.2009.12.146.

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19

Okano, Satoshi, Akira Yasui, Kiyoshi Hayasaka, and Osamu Nakajima. "Unique food-entrained circadian rhythm in cysteine414-alanine mutant mCRY1 transgenic mice." Sleep and Biological Rhythms 14, no. 3 (January 29, 2016): 261–69. http://dx.doi.org/10.1007/s41105-016-0050-1.

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20

Kurabayashi, Nobuhiro, Tsuyoshi Hirota, Yuko Harada, Mihoko Sakai, and Yoshitaka Fukada. "Phosphorylation of mCRY2 at Ser557 in the Hypothalamic Suprachiasmatic Nucleus of the Mouse." Chronobiology International 23, no. 1-2 (January 2006): 129–34. http://dx.doi.org/10.1080/07420520500464478.

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21

Harada, Yuko, Mihoko Sakai, Nobuhiro Kurabayashi, Tsuyoshi Hirota та Yoshitaka Fukada. "Ser-557-phosphorylated mCRY2 Is Degraded upon Synergistic Phosphorylation by Glycogen Synthase Kinase-3β". Journal of Biological Chemistry 280, № 36 (24 червня 2005): 31714–21. http://dx.doi.org/10.1074/jbc.m506225200.

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22

Toro Carvajal, Luis Alberto. "Modelo computacional representacional de la matemática (mcrmat)." ÁNFORA 17, no. 28 (September 22, 2016): 151–78. http://dx.doi.org/10.30854/anf.v17.n28.2010.104.

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Este artículo presenta lo que el autor denomina modelo computacionalrepresentacional de la matemática (MCRMAT), su importancia teórica para la educación matemática y su relación con el uso de tecnologías informáticas en la enseñanza de tal ciencia. A tal efecto, y desde el punto de vista de la ciencia cognitiva, se hace un estudio de lo que son las representaciones, lo mismo que se explica el modelo computacional-representacional de la mente (MCRM).

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23

Hashimoto, Kenji, Ayesh Perera, Naofumi Sugaya, Yoshitaka Ogita, Mikiko Nakamura, Sheila Rossi, Takahiro Ishiguro, et al. "A phase I dose escalation (DE) and cohort expansion (CE) study of ERY974, an anti-glypican 3 (GPC3)/CD3 bispecific antibody, in patients with advanced solid tumors." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS3112. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps3112.

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TPS3112 Background: Bispecific antibodies to facilitate T-cell directed cytotoxicity (TDCC) is a proven therapy strategy in cancer. ERY974 is a humanized IgG4 bispecific antibody designed to simultaneously bind to cytotoxic T-cell CD3 receptors and GPC3 (a glycoprotein expressed on cell surface of several tumors) to elicit T-cell activation and TDCC. The objectives of this multi-country, phase 1 study of ERY974 is to determine the maximum tolerated dose (MTD) and to perform a preliminary assessment of anti-tumor activity in patients with solid tumors expressing GPC3. Methods: ERY974 is dosed IV weekly. All patients receive premedication with dexamethasone (DEX) prior to 1st and 2nd ERY974 dose. DE uses an accelerated titration design (ATD), then a modified continual reassessment method (mCRM) described by one-parameter logistic model, to determine MTD, where DLT occurrence rate is 0.25. Combining ATD and mCRM is to permit rapid dose escalation whilst minimizing patient numbers exposed to sub-therapeutic doses, and to accurately determine MTD. Once grade 2 (G2) cytokine release syndrome (CRS) is observed, DEX is increased. If ≥G2 CRS is again observed, then at all subsequent doses the 1st dose of ERY974 is fixed at the last dose level when < G2 CRS was not seen, DE proceeds with the 2nd dose. ATD commences with n = 1, increasing to n = 3 once drug-related ≥G2 toxicity is seen. mCRM starts after 1st dose limiting toxicity (DLT), with the modifications of at least 3 patients required to dose escalate and up to 1.5x increment to minimize risk of toxicity. CE has 3 arms: GPC3+ gastric/gastroesophageal junction adenocarcinoma; GPC3+ squamous esophageal cancer; and other GPC3+ tumors. A 2-stage design is used to allow CE to stop early for futility. Subjects are adults with histologically confirmed, measurable malignant solid tumors and/or metastatic disease not amenable to standard therapy, and life expectancy ≥3 months. Patients with > 1cm or > 1 brain metastasis, current/previous interstitial lung disease, and acute/chronic infection are excluded. 3 cohorts have been completed without DLT. Cohort 4 began in January 2017. Clinical trial information: NCT02748837.

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Azarianpour Esfahani, Sepideh, Germán Corredor, Kaustav Bera, PingFu Fu, Amy Joehlin-Price, Haider Mahdi, and Anant Madabhushi. "Computerized features of spatial arrangement of tumor-infiltrating lymphocytes from H&E images predicts survival and response to checkpoint inhibitors in gynecologic cancers." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 6074. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.6074.

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6074 Background: Immune checkpoint inhibitors (ICI) have demonstrated success in solid tumors. In gynecologic cancers (GC), the response rate is still low (~10-15%) except in MSI-H endometrial cancer (~ 50%). Current biomarkers (e.g. PDL1 expression) have limited utility in identifying benefit from ICI in GC. In this work we evaluated the ability of computational measurements of spatial arrangement of tumor infiltrating lymphocytes (TIL) from H&E slide images in predicting overall survival (OS) and response to ICI in ovarian, cervical and endometrial cancers. Methods: The study included 151 patients, including 102 ovarian carcinomas treated with surgery and chemotherapy (D1) and another set (D2) of n=49 patients (n=14 ovarian, n=27 endometrial and n=8 cervical), treated with different ICI agents (Pembrolizumab, Nivolumab, Ipilimumab, Avelumab) in the second line setting. Progressors and non-progressors in D2 were classified according to clinical improvement and radiologic assessment by RECIST. A machine learning approach was employed to identify tumor regions on the diagnostic slides from D1 and D2 and then used to automatically identify TILs within the tumor regions. Subsequently machine learning was used to define TIL clusters based on TIL proximity, and graph network theory was used to capture measurements relating to spatial arrangement of TIL clusters. The multivariable Cox regression model (MCRM) was trained on n=51 patients from D1 to predict OS and then independently evaluated in predicting (1) OS on the hold-out n=51 patients in D1 and (2) response and progression-free survival (PFS) in D2. Results: Statistical analysis identified 7 prognostic features relating to interaction of TIL clusters with cancer nuclei. MCRM was prognostic of OS on the n=51 hold out patients in D1 (hazard ratio (HR)=2.06, 95% confidence interval [1.04- 4.07], p=0.008) and predictive of PFS in D2 (HR=2.24, CI=[1.13-4.44], p=0.03). The AUC for MCRM in predicting progression in D2 was 82%. Conclusions: Computerized features of spatial arrangement of TILs on H&E images were prognostic of OS and PFS and predicted response to ICI in three gynecological cancers. These findings need to be validated in larger, multi-site validation sets. [Table: see text]

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25

Yagita, Kazuhiro, Filippo Tamanini, Maya Yasuda, Jan H. J. Hoeijmakers, Gijsbertus T. J. van der Horst, and Hitoshi Okamura. "Nucleocytoplasmic shuttling and mCRY-dependent inhibition of ubiquitylation of the mPER2 clock protein." EMBO Journal 21, no. 6 (March 15, 2002): 1301–14. http://dx.doi.org/10.1093/emboj/21.6.1301.

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Loop, Susanne, Mathias Katzer, and Tomas Pieler. "mPER1‐mediated nuclear export of mCRY1/2 is an important element in establishing circadian rhythm." EMBO reports 6, no. 4 (April 2005): 341–47. http://dx.doi.org/10.1038/sj.embor.7400372.

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Lai, Yong, Guangqing Huang, Shengzhong Chen, Shaotao Lin, Wenjun Lin, and Jixin Lyu. "Land Use Dynamics and Optimization from 2000 to 2020 in East Guangdong Province, China." Sustainability 13, no. 6 (March 21, 2021): 3473. http://dx.doi.org/10.3390/su13063473.

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Anthropogenic land-use change is one of the main drivers of global environmental change. China has been on a fast track of land-use change since the Reform and Opening-up policy in 1978. In view of the situation, this study aims to optimize land use and provide a way to effectively coordinate the development and ecological protection in China. We took East Guangdong (EGD), an underdeveloped but populous region, as a case study. We used land-use changes indexes to demonstrate the land-use dynamics in EGD from 2000 to 2020, then identified the hot spots for fast-growing areas of built-up land and simulated land use in 2030 using the future land-use simulation (FLUS) model. The results indicated that the cropland and the built-up land changed in a large proportion during the study period. Then we established the ecological security pattern (ESP) according to the minimal cumulative resistance model (MCRM) based on the natural and socioeconomic factors. Corridors, buffer zones, and the key nodes were extracted by the MCRM to maintain landscape connectivity and key ecological processes of the study area. Moreover, the study showed the way to identify the conflict zones between future built-up land expansion with the corridors and buffer zones, which will be critical areas of consideration for future land-use management. Finally, some relevant policy recommendations are proposed based on the research result.

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Negahban, Arash, Dan J. Kim, and Changsu Kim. "Unleashing the Power of mCRM: Investigating Antecedents of Mobile CRM Values from Managers’ Viewpoint." International Journal of Human–Computer Interaction 32, no. 10 (June 16, 2016): 747–64. http://dx.doi.org/10.1080/10447318.2016.1189653.

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Rodriguez, Michael, and Stefanie Boyer. "The impact of mobile customer relationship management (mCRM) on sales collaboration and sales performance." Journal of Marketing Analytics 8, no. 3 (August 1, 2020): 137–48. http://dx.doi.org/10.1057/s41270-020-00087-3.

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Cao, Cheng-Xi, Ren-Zhi Li, Shu-Lin Zhuo, Wen-Kui Chen, and Yi-Tai Qian. "Stable colloid of Co(OH)2 prepared by moving chemical reaction boundary method (MCRBM) in agarose gel." Colloids and Surfaces A: Physicochemical and Engineering Aspects 180, no. 1-2 (May 2001): 17–21. http://dx.doi.org/10.1016/s0927-7757(00)00740-8.

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Okano, Satoshi, Akira Yasui, Shin-ichiro Kanno, Kennichi Satoh, Masahiko Igarashi, and Osamu Nakajima. "Karyopherin Alpha 2-Expressing Pancreatic Duct Glands and Intra-Islet Ducts in Aged Diabetic C414A-Mutant-CRY1 Transgenic Mice." Journal of Diabetes Research 2019 (April 24, 2019): 1–11. http://dx.doi.org/10.1155/2019/7234549.

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Our earlier studies demonstrated that cysteine414- (zinc-binding site of mCRY1-) alanine mutant mCRY1 transgenic mice (Tg mice) exhibit diabetes characterized by the reduction of β-cell proliferation and by β-cell dysfunction, presumably caused by senescence-associated secretory phenotype- (SASP-) like characters of islets. Earlier studies also showed that atypical duct-like structures in the pancreas developed age-dependently in Tg mice. Numerous reports have described that karyopherin alpha 2 (KPNA2) is highly expressed in cancers of different kinds. However, details of the expression of KPNA2 in pancreatic ductal atypia and in normal pancreatic tissues remain unclear. To assess the feature of the expression of KPNA2 in the development of the ductal atypia and islet architectures, we scrutinized the pancreas of Tg mice histopathologically. Results showed that considerable expression of KPNA2 was observed in pancreatic β-cells, suggesting its importance in maintaining the functions of β-cells. In mature stages, the level of KPNA2 expression was lower in islets of Tg mice than in wild-type controls. At 4 weeks, the expression levels of KPNA2 in islets of Tg mice were the same as those in wild-type controls. These results suggest that the reduction of KPNA2 might contribute to β-cell dysfunction in mature Tg mice. Additionally, the formation of mucin-producing intra-islet ducts, islet fibrosis, and massive T cell recruitment to the islet occurred in aged Tg mice. In exocrine areas, primary pancreatic intraepithelial neoplasias (PanINs) with mucinous pancreatic duct glands (PDGs) emerged in aged Tg mice. High expression of KPNA2 was observed in the ductal atypia. By contrast, KPNA2 expression in normal ducts was quite low. Thus, upregulation of KPNA2 seemed to be correlated with progression of the degree of atypia in pancreatic ductal cells. The SASP-like microenvironment inside islets might play stimulatory roles in the formation of ductal metaplasia inside islets and in islet fibrosis in Tg mice.

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Yamaguchi, Shun, Shigeru Mitsui, Lily Yan, Kazuhiro Yagita, Shigeru Miyake, and Hitoshi Okamura. "Role of DBP in the Circadian Oscillatory Mechanism." Molecular and Cellular Biology 20, no. 13 (July 1, 2000): 4773–81. http://dx.doi.org/10.1128/mcb.20.13.4773-4781.2000.

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ABSTRACT Transcript levels of DBP, a member of the PAR leucine zipper transcription factor family, exhibit a robust rhythm in suprachiasmatic nuclei, the mammalian circadian center. Here we report that DBP is able to activate the promoter of a putative clock oscillating gene,mPer1, by directly binding to the mPer1promoter. The mPer1 promoter is cooperatively activated by DBP and CLOCK-BMAL1. On the other hand, dbp transcription is activated by CLOCK-BMAL1 through E-boxes and inhibited by the mPER and mCRY proteins, as is the case for mPer1. Thus, a clock-controlled dbp gene may play an important role in central clock oscillation.

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Huang, Xing, Xiang Chen, Yong Shuai, Yuan Yuan, Tong Zhang, Bingxi Li, and Heping Tan. "Heat transfer analysis of solar-thermal dissociation of NiFe 2 O 4 by coupling MCRTM and FVM method." Energy Conversion and Management 106 (December 2015): 676–86. http://dx.doi.org/10.1016/j.enconman.2015.10.013.

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Sakakida, Yoko, Yoichi Miyamoto, Emi Nagoshi, Makoto Akashi, Takahiro J. Nakamura, Takayoshi Mamine, Megumi Kasahara, Yasuhiro Minami, Yoshihiro Yoneda та Toru Takumi. "Importin α/β Mediates Nuclear Transport of a Mammalian Circadian Clock Component, mCRY2, Together with mPER2, through a Bipartite Nuclear Localization Signal". Journal of Biological Chemistry 280, № 14 (2 лютого 2005): 13272–78. http://dx.doi.org/10.1074/jbc.m413236200.

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Naruse, Yoshihisa, Kentaro Oh-hashi, Norio Iijima, Midori Naruse, Hideyo Yoshioka, and Masaki Tanaka. "Circadian and Light-Induced Transcription of Clock Gene Per1 Depends on Histone Acetylation and Deacetylation." Molecular and Cellular Biology 24, no. 14 (July 15, 2004): 6278–87. http://dx.doi.org/10.1128/mcb.24.14.6278-6287.2004.

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ABSTRACT Circadian clock genes are regulated through a transcriptional-translational feedback loop. Alterations of the chromatin structure by histone acetyltransferases and histone deacetylases (HDACs) are commonly implicated in the regulation of gene transcription. However, little is known about the transcriptional regulation of mammalian clock genes by chromatin modification. Here, we show that the state of acetylated histones fluctuated in parallel with the rhythm of mouse Per1 (mPer1) or mPer2 expression in fibroblast cells and liver. Mouse CRY1 (mCRY1) repressed transcription with HDACs and mSin3B, which was relieved by the HDAC inhibitor trichostatin A (TSA). In turn, TSA induced endogenous mPer1 expression as well as the acetylation of histones H3 and H4, which interacted with the mPer1 promoter region in fibroblast cells. Moreover, a light pulse stimulated rapid histone acetylation associated with the promoters of mPer1 or mPer2 in the suprachiasmatic nucleus (SCN) and the binding of phospho-CREB in the CRE of mPer1. We also showed that TSA administration into the lateral ventricle induced mPer1 and mPer2 expression in the SCN. Taken together, these data indicate that the rhythmic transcription and light induction of clock genes are regulated by histone acetylation and deacetylation.

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Alenkov, V., O. A. Buzanov, N. Khanbekov, V. N. Kornoukhov, H. Kraus, V. B. Mikhailik, and V. A. Shuvaeva. "Application of the Monte-Carlo refractive index matching (MCRIM) technique to the determination of the absolute light yield of a calcium molybdate scintillator." Journal of Instrumentation 8, no. 06 (June 6, 2013): P06002. http://dx.doi.org/10.1088/1748-0221/8/06/p06002.

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Akashi, Makoto, Yoshiki Tsuchiya, Takao Yoshino та Eisuke Nishida. "Control of Intracellular Dynamics of Mammalian Period Proteins by Casein Kinase I ε (CKIε) and CKIδ in Cultured Cells". Molecular and Cellular Biology 22, № 6 (15 березня 2002): 1693–703. http://dx.doi.org/10.1128/mcb.22.6.1693-1703.2002.

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ABSTRACT Recent studies have shown that casein kinase I ε (CKIε) is an essential regulator of the mammalian circadian clock. However, the detailed mechanisms by which CKIε regulates each component of the circadian negative-feedback loop have not been fully defined. We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIε and CKIδ. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIε and CKIδ are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIε. CKIε and CKIδ affected the inhibitory effect of mPer proteins on the transcriptional activity of BMAL1-CLOCK, but the inhibitory effect of mCry proteins on the activity of BMAL1-CLOCK was unaffected. These results suggest that CKIε and CKIδ regulate the mammalian circadian autoregulatory loop by controlling both protein turnover and subcellular localization of mPer proteins.

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Shearman, Lauren P., Xiaowei Jin, Choogon Lee, Steven M. Reppert, and David R. Weaver. "Targeted Disruption of the mPer3 Gene: Subtle Effects on Circadian Clock Function." Molecular and Cellular Biology 20, no. 17 (September 1, 2000): 6269–75. http://dx.doi.org/10.1128/mcb.20.17.6269-6275.2000.

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ABSTRACT Neurons in the mammalian suprachiasmatic nucleus (SCN) contain a cell-autonomous circadian clock that is based on a transcriptional-translational feedback loop. The basic helix-loop-helix–PAS proteins CLOCK and BMAL1 are positive regulators and drive the expression of the negative regulators CRY1 and CRY2, as well as PER1, PER2, and PER3. To assess the role of mouse PER3 (mPER3) in the circadian timing system, we generated mice with a targeted disruption of the mPer3 gene. Western blot analysis confirmed the absence of mPER3-immunoreactive proteins in mice homozygous for the targeted allele. mPer1,mPer2, mCry1, and Bmal1 RNA rhythms in the SCN did not differ between mPER3-deficient and wild-type mice. Rhythmic expression of mPer1 and mPer2 RNAs in skeletal muscle also did not differ between mPER3-deficient and wild-type mice. mPer3 transcripts were rhythmically expressed in the SCN and skeletal muscle of mice homozygous for the targeted allele, but the level of expression of the mutant transcript was lower than that in wild-type controls. Locomotor activity rhythms in mPER3-deficient mice were grossly normal, but the circadian cycle length was significantly (0.5 h) shorter than that in controls. The results demonstrate that mPer3 is not necessary for circadian rhythms in mice.

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Froy, Oren, Nava Chapnik та Ruth Miskin. "Long-lived αMUPA transgenic mice exhibit pronounced circadian rhythms". American Journal of Physiology-Endocrinology and Metabolism 291, № 5 (листопад 2006): E1017—E1024. http://dx.doi.org/10.1152/ajpendo.00140.2006.

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Robust biological rhythms have been shown to affect life span. Biological clocks can be entrained by two feeding regimens, restricted feeding (RF) and caloric restriction (CR). RF restricts the time of food availability, whereas CR restricts the amount of calories with temporal food consumption. CR is known to retard aging and extend life span of animals via yet-unknown pathways. We hypothesize that resetting the biological clock could be one possible mechanism by which CR extends life span. Because it is experimentally difficult to uncouple calorie reduction from temporal food consumption, we took advantage of the murine urokinase-like plasminogen activator (αMUPA) transgenic mice overexpressing a serine protease implicated in brain development and plasticity; they exhibit spontaneously reduced eating and increased life span. Quantitative real-time PCR analysis revealed that αMUPA mice exhibit robust expression of the clock genes mPer1, mPer2, mClock, and mCry1 but not mBmal1 in the liver. We also found changes in the circadian amplitude and/or phase of clock-controlled output systems, such as feeding behavior, body temperature, and enteric cryptdin expression. A change in the light-dark regimen led to modified clock gene expression and abrogated circadian patterns of food intake in wild-type (WT) and αMUPA mice. Consequently, food consumption of WT mice increased, whereas that of αMUPA mice remained the same, indicating that reduced food intake occurs upstream and independently of the biological clock. Thus we surmise that CR could lead to pronounced and synchronized biological rhythms. Because the biological clock controls mitochondrial, hormonal, and physiological parameters, system synchronicity could lead to extended life span.

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Benavides Córdoba, Vicente, and Esther C. Wilches Luna. "Mudanças na pontuação do índice Bode em pacientes com DPOC, antes e depois de reabilitação pulmonar." Revista Ciencias de la Salud 16, no. 1 (January 31, 2018): 101. http://dx.doi.org/10.12804/revistas.urosario.edu.co/revsalud/a.6493.

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Introducción: la rehabilitación pulmonar ha sido avalada como herramienta de tratamiento en la enfermedad pulmonar obstructiva crónica —Epoc—. Aunque existen varios programas en nuestro medio, son escasos los reportes que evalúen el impacto de estos. El índice Bode es una escala multidimensional que refleja el impacto de los factores pulmonar y extrapulmonar en el pronóstico y la sobrevida; la rehabilitación pulmonar mejora algunos componentes del índice. El objetivo fue describir los cambios en la puntuación del índice Bode en pacientes con Epoc, antes y después de asistir a un programa de rehabilitación pulmonar. Materiales y métodos: estudio descriptivo, retrospectivo-longitudinal. Se seleccionaron registros diligenciados en el 2009 y el 2010. Se incluyeron 24 pacientes con Epoc que asistieron durante ocho semanas a un hospital nivel III de la ciudad de Cali, Colombia. Se realizó el análisis descriptivo que incluyó frecuencias, medidas de tendencia central y dispersión. El análisis inferencial se basó en la comparación de la evaluación inicial y nal de las variables de estudio. Resultados: la puntuación total del índice Bode, la tolerancia al esfuerzo, la medida con test de caminata y la disnea medida con la escala del Modified Medical Research Council —Mcrm— tuvieron reducciones significativas (p > 0,05). Conclusiones: se observó que la rehabilita- ción pulmonar reduce la puntuación del índice bode en pacientes con Epoc.

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Rinaldi, D. A., H. A. Burris, F. A. Dorr, J. R. Woodworth, J. G. Kuhn, J. R. Eckardt, G. Rodriguez, S. W. Corso, S. M. Fields, and C. Langley. "Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation." Journal of Clinical Oncology 13, no. 11 (November 1995): 2842–50. http://dx.doi.org/10.1200/jco.1995.13.11.2842.

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PURPOSE To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor. PATIENTS AND METHODS Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer. CONCLUSION The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.

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Gao, Chao, Martijn J. Booij, and Yue-Ping Xu. "Assessment of extreme flows and uncertainty under climate change: disentangling the uncertainty contribution of representative concentration pathways, global climate models and internal climate variability." Hydrology and Earth System Sciences 24, no. 6 (June 23, 2020): 3251–69. http://dx.doi.org/10.5194/hess-24-3251-2020.

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Abstract. Projections of streamflow, particularly of extreme flows under climate change, are essential for future water resources management and the development of adaptation strategies to floods and droughts. However, these projections are subject to uncertainties originating from different sources. In this study, we explored the possible changes in future streamflow, particularly for high and low flows, under climate change in the Qu River basin, eastern China. ANOVA (analysis of variance) was employed to quantify the contribution of different uncertainty sources from RCPs (representative concentration pathways), GCMs (global climate models) and internal climate variability, using an ensemble of 4 RCP scenarios, 9 GCMs and 1000 simulated realizations of each model–scenario combination by SDRM-MCREM (a stochastic daily rainfall model coupling a Markov chain model with a rainfall event model). The results show that annual mean flow and high flows are projected to increase and that low flows will probably decrease in 2041–2070 (2050s) and 2071–2100 (2080s) relative to the historical period of 1971–2000, suggesting a higher risk of floods and droughts in the future in the Qu River basin, especially for the late 21st century. Uncertainty in mean flows is mostly attributed to GCM uncertainty. For high flows and low flows, internal climate variability and GCM uncertainty are two major uncertainty sources for the 2050s and 2080s, while for the 2080s, the effect of RCP uncertainty becomes more pronounced, particularly for low flows. The findings in this study can help water managers to become more knowledgeable about and get a better understanding of streamflow projections and support decision making regarding adaptations to a changing climate under uncertainty in the Qu River basin.

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Mitchell, Peter, and Charles Arthur. "Ha Makotoko: Later Stone Age Occupation across the Pleistocene/Holocene Transition in Western Lesotho." Journal of African Archaeology 12, no. 2 (November 1, 2014): 205–32. http://dx.doi.org/10.3213/2191-5784-10255.

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Stratigraphically extensive sites with good organic preservation that date to the Pleistocene/Holocene transition are rare in southern Africa outside the Fynbos Biome of the Cape. However, the Caledon Valley, which forms Lesotho’s western border with South Africa, boasts an unusual concentration of such sites, especially in its central portion. Archaeological fieldwork ahead of the impoundment of the Metolong Dam provided a renewed — and final — opportunity to investigate two of these sites, Ha Makotoko and Ntloana Tšoana, as part of a much larger study of the area’s cultural heritage by the Metolong Cultural Heritage Management (MCRM) Project. This paper reports on the assemblages from the earlier part of the Later Stone Age sequence from Ha Makotoko. As well as confirming the presence of two distinct phases of occupation by makers of the Oakhurst Complex during the early Holocene, new excavations identified an earlier , Robberg Industry occupation of terminal Pleistocene age. These assemblages are described and those of early Holocene date compared to observations from the earlier 1989 excavation at Ha Makotoko. Strongly defined patterning in the overall organisation of the use of space at the site is recognised, along with the potential to begin exploring such sites to answer questions about social practices relevant at a human timescale. Comparison of Ha Makotoko with other sites in the Caledon Valley suggests that such opportunities may also exist elsewhere in the region and reinforces its significance for studies of the Pleistocene/Holocene transition at a sub-continental scale.

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Deppisch, Peter, Charlotte Helfrich-Förster, and Pingkalai R. Senthilan. "The Gain and Loss of Cryptochrome/Photolyase Family Members during Evolution." Genes 13, no. 9 (September 8, 2022): 1613. http://dx.doi.org/10.3390/genes13091613.

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The cryptochrome/photolyase (CRY/PL) family represents an ancient group of proteins fulfilling two fundamental functions. While photolyases repair UV-induced DNA damages, cryptochromes mainly influence the circadian clock. In this study, we took advantage of the large number of already sequenced and annotated genes available in databases and systematically searched for the protein sequences of CRY/PL family members in all taxonomic groups primarily focusing on metazoans and limiting the number of species per taxonomic order to five. Using BLASTP searches and subsequent phylogenetic tree and motif analyses, we identified five distinct photolyases (CPDI, CPDII, CPDIII, 6-4 photolyase, and the plant photolyase PPL) and six cryptochrome subfamilies (DASH-CRY, mammalian-type MCRY, Drosophila-type DCRY, cnidarian-specific ACRY, plant-specific PCRY, and the putative magnetoreceptor CRY4. Manually assigning the CRY/PL subfamilies to the species studied, we have noted that over evolutionary history, an initial increase of various CRY/PL subfamilies was followed by a decrease and specialization. Thus, in more primitive organisms (e.g., bacteria, archaea, simple eukaryotes, and in basal metazoans), we find relatively few CRY/PL members. As species become more evolved (e.g., cnidarians, mollusks, echinoderms, etc.), the CRY/PL repertoire also increases, whereas it appears to decrease again in more recent organisms (humans, fruit flies, etc.). Moreover, our study indicates that all cryptochromes, although largely active in the circadian clock, arose independently from different photolyases, explaining their different modes of action.

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Rabbi, Hashim, Md Mamunur Rashid, AHM Tanvir Ahmed, Mirza Shamsul Arefin, Sarder Rizwan Nayeem, Mohammad Ali, HA Nazmul Hakim, et al. "Management strategies of potentially resectable colorectal liver metastases in a cohort of Bangladeshi patients." BIRDEM Medical Journal 9, no. 3 (September 11, 2019): 207–12. http://dx.doi.org/10.3329/birdem.v9i3.43084.

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Background: Colorectal cancer with liver metastases (CRLM) is stage IV disease. Only 60% patients present with palpable liver or a liver mass and at laparotomy 80% hepatic metastases can be detected. Synchronous CRLM (SCRRLM) is indicative of poor prognosis than metachronous (MCRLM) counterpart. Only 13-15% of SCLM are eligible for curative resection. Surgical intervention offers long term cure with overall survival in 37-58% patients. This study was designed to validate different approaches of management to patients with CRLM in Bangladeshi patients. Methods: In this prospective observational study, we observed different management approaches in 41 Bangladeshi individuals with CRLM from January 2010 to January 2018 in different tertiary care hospitals of Dhaka. They were thoroughly evaluated and prepared for surgical resection. After detection both synchronous and metachronous CRLM, patients were treated surgically with colonic resection and liver resection with simultaneous approach, lesion first approach, liver first approach. Intraoperative ultrasound was valuable in localization of liver lesions. Patients were followed up for a minimum 6 months to maximum period of 61 months. Results: The study included 41 patients between ages of 21 to 70 years, of them 22 (53.65%) males and 19 (46.34%) were female. Among them, 19 patients (46.34%) had synchronous lesion and 22 (53.66%) had metachronous lesion. Neoadjuvant therapy was given in 9 (21.95%) patients. All the patients received adjuvant therapy. Multiple metastetectomy was done in 31 (75.60%) patients. In our series, following margin negative hepatic resection,14 (34.14%) patients survived 3 years and 3(7.31 %) patients survived 5 years. Conclusion: CRLM signifies an advanced disease at presentation. Hepatic resection following resection of colorectal primary is curative. Simultaneous liver with colonic resection is safe and effective in cases of small hepatic metastases. Birdem Med J 2019; 9(3): 207-212

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Dougherty, Thomas B., Vivian H. Porche, and Peter F. Thall. "Maximum Tolerated Dose of Nalmefene in Patients Receiving Epidural Fentanyl and Dilute Bupivacaine for Postoperative Analgesia." Anesthesiology 92, no. 4 (April 1, 2000): 1010–16. http://dx.doi.org/10.1097/00000542-200004000-00018.

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Background This study investigated the ability of the modified continual reassessment method (MCRM) to determine the maximum tolerated dose of the opioid antagonist nalmefene, which does not reverse analgesia in an acceptable number of postoperative patients receiving epidural fentanyl in 0.075% bupivacaine. Methods In the postanesthetic care unit, patients received a single intravenous dose of 0.25, 0.50, 0.75, or 1.00 microg/kg nalmefene. Reversal of analgesia was defined as an increase in pain score of two or more integers above baseline on a visual analog scale from 0 through 10 after nalmefene administration. Patients were treated in cohorts of one, starting with the lowest dose. The maximum tolerated dose of nalmefene was defined as that dose, among the four studied, with a final mean probability of reversal of anesthesia (PROA) closest to 0.20 (ie., a 20% chance of causing reversal). The modified continual reassessment method is an iterative Bayesian statistical procedure that, in this study, selected the dose for each successive cohort as that having a mean PROA closest to the preselected target PROA of 0.20. Results The modified continual reassessment method repeatedly updated the PROA of each dose level as successive patients were observed for presence or absence of ROA. After 25 patients, the maximum tolerated dose of nalmefene was selected as 0.50 microg/kg (final mean PROA = 0.18). The 1.00-microg/kg dose was never tried because its projected PROA was far above 0.20. Conclusions The modified continual reassessment method facilitated determination of the maximum tolerated dose ofnalmefene . Operating characteristics of the modified continual reassessment method suggest it may be an effective statistical tool for dose-finding in trials of selected analgesic or anesthetic agents.

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Karantza-Wadsworth, V., M. Stein, A. Tan, J. Mehnert, E. Poplin, Y. Lin, E. White, and R. S. DiPaola. "Rationally designed treatment for solid tumors with MAPK pathway activation." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2532. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2532.

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2532 Background: Preclinical studies shed light to the mechanism conferring paclitaxel resistance in solid tumors with active Ras/Raf/Mitogen-Activated Protein Kinase (MAPK) pathway, and determined a molecular mechanism by which addition of the proteasome inhibitor bortezomib abrogated this resistance, enabling tumor regression in animals in vivo. Methods: A Phase I study was contacted to determine the MTD of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors were treated with weekly paclitaxel and bortezomib. Six patients had NSCLC; 4, colon cancer; 2, pancreatic; 2, melanoma; 1, breast; 1, ovarian. Patients with baseline neuropathy greater than or equal to Grade 1 were excluded. The starting dose was 40 mg/m2 for paclitaxel and 0.7 mg/m2 for bortezomib. A modified continual reassessment method (MCRM) was used for dose escalation with 3-patient cohorts treated at each dose level. The Target Toxicity Level (probability of DLT at the MTD) was set at 25%. Maximum dose escalation was no more than 75% of the previous SED level, if no Grade 3 hematologic toxicity or DLT were observed. Otherwise, the maximum dose escalation was no more than 50% of the previous SED level. The process continued until SED changes were no more than 10% for two consecutive cohorts. Results: The MTD for the combinatorial treatment was reached at 60 mg/m2 paclitaxel and 1.0 mg/m2 bortezomib. Of 15 evaluable patients, 1 patient with paclitaxel-resistant NSCLC had PR and 5 patients (2, NSCLC; 1, pancreatic; 1, colon; 1, ovarian) had stable disease. Median TTP was 2.3 months (0.8 to 6 months). Three NSCLC patients achieved TTP longer than 5 months. The combination of paclitaxel and bortezomib was relatively well tolerated. Paclitaxel PK parameters are being determined, and paraffin-embedded tumor specimens are being evaluated for MAPK pathway activation by IHC for phospho-ERK. Results will be correlated with clinical response. Conclusions: The MTD for the proposed combinatorial treatment is 60 mg/m2 for paclitaxel and 1.0 mg/m2 for bortezomib, and is relatively well tolerated. Combination of paclitaxel with bortezomib is effective in taxane-resistant NSCLC, and worthy of further investigation. No significant financial relationships to disclose.

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Frappaz, D., J. Pierga, J. Bay, M. Fabbro, L. Djafari, and M. Sunyach. "Phase I of high dose (HD) temozolomide (TMZ) with peripheral blood stem cell support (PBSCS) rescue in recurrent high grade glioma (HGG)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 12518. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.12518.

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12518 Background: Despite improvements obtained with frontline treatments prognosis of recurrent HGG still remains dismal. HD chemotherapy (CT) suggested a dose-effect relationship in lymphoma and germ cell tumors. HD of TMZ could be a promising way to overcome resistance of HGG to standard schedule of CT Methods: This phase I had as principal objective to determine the Maximal Tolerated Dose (MTD) of HD of TMZ with PBSCS rescue in patients with recurrent HGG under 60 year. The MTD was defined as dose level which 50% of patients (pts) treated experienced a DLT (Dose Limiting Toxicity).The dose escalation was planned for eight dose levels from 300 to 650mg/m2/day over 5 days with CSP reinfusion at D7 according to the Modified Continual Reassessment Method (MCRM). Treatment was administered for one cycle. Results: Eighteen eligible pts were treated with HD of TMZ, all had received prior radiotherapy, 11 pts previous CT. Overall HD TMZ was well tolerated for the 7 evaluated dose levels. The MTD was not yet reached. Not dose limiting toxicities were reported in 12 pts: grade 2: fatigue (6pts), cephalalgia (3pts), nausea (3pts) , skin eruption (2pts), mucositis, FUO, vomiting, diarrhea, zoster, dental abcess, lung infection, septicemia, hepatic. grade 3 bilirubinemia, grade 4 neutropenia (13pts) and thrombocytopenia (4pts). Dose Limiting Toxicities were reported in 2 pts, gr3 cytolysis at level 3 (400mg/m2/day ) 1pt and gr 3 arthritis at level 7 (600mg/m2) 1pt respectively . Main hematological toxicities were gr 4 neutropenia in 13 pts median duration was 8 days, 4 pts had gr4 thrombocytopenia lasting 5 days. All patients were evaluable for tumor response, 2 partial responses were observed at 550 and 600mg/m2 level, 5 pts had a stabilization and a disease progression was reported in 11 patients. Conclusions: This interim analysis demonstrated that HD of TMZ with CSP reinfusion is feasible and well tolerated in patients with recurrent HGG. Nevertheless limited activity reported could be related to a less depletion of O6 alkylguanine transferase with HD than with a protracted schedule. Accrual is still ongoing. No significant financial relationships to disclose.

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Koolen, S., P. O. Witteveen, I. Garcia-Ribas, S. Callies, V. Andre, R. H. Kronemeijer, A. Nol, J. H. Beijnen, E. E. Voest, and J. H. Schellens. "Phase I study of oral gemcitabine prodrug (LY2334737) alone and in combination with erlotinib in patients (pts) with advanced solid tumors." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2576. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2576.

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2576 Background: LY2334737 (LY) is an orally available valproic acid prodrug of gemcitabine that was developed to overcome the extensive first-pass metabolism of gemcitabine to 2',2'-difluorodeoxyuridine (dFdU). The objectives of this study were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics (PK) of LY as monotherapy and in combination with erlotinib. Methods: Eligible pts had ECOG PS < 2 and adequate hematologic, renal and hepatic function. In Arm A, LY was given daily for 14 days in a 3-week cycle. Pts assigned to Arm B also received erlotinib daily 100 mg continuously. Dose escalation was based on observed toxicity and the modified continual reassessment method (mCRM). The dose was maximally increased by 100% depending on the toxicity observed in the previous cohort. PK of LY, gemcitabine, dFdU and intracellular metabolites were determined. Results: 33 pts (21 m, 12 f, median age 60 yrs (range 24–81)) were treated at 5 different dose-levels (range 5–50 mg/day). Pts received a median of 3 cycles (range 2–17). Three out of 7 pt treated with 50 mg experienced 5 dose limiting toxicities (DLT). DLTs observed at 40 and 50 mg include fatigue (4 pt), thrombocytopenia (1 pt), GGT elevation (1 pt), AST/ALT elevation (1 pt), fever (1 pt), and pulmonary embolism (1 pt). One death was possibly related to LY intake. This pt, treated with 40 mg LY, developed on day 15 dyspnea, hypovolemic shock, and suddenly died. No grade 3 or 4 toxicities were reported at dose-levels < 40 mg. The most common adverse events were fatigue, vomiting, nausea, pyrexia, anorexia, and diarrhea. Two pts with mesothelioma were stable for > 9 months. One pt with refractory prostate cancer presented a PSA CR as assessed by investigator. The PK show dose-proportional increase in exposure of both LY and gemcitabine. Both LY and gemcitabine are rapidly cleared, thus no accumulation occurs. The metabolite dFdU accumulates due to its long half life. Conclusions: LY displays linear PK. The dose level of 50-mg is non-tolerable and 40-mg is being confirmed as the MTD as single agent and in combination with 100 mg erlotinib. Antitumor activity warrants further development. Pt accrual is ongoing. [Table: see text]

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Juergens, Rosalyn A., Quincy S. Chu, Daniel John Renouf, Scott Andrew Laurie, Daniela Purcea, Elaine McWhirter, Diane Arndt, et al. "A dose-finding study of the SMAC mimetic Debio 1143 when given in combination with avelumab to patients with advanced solid malignancies." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2599. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2599.

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2599 Background: Second mitochondria-derived activator of caspase (SMAC) mimetics regulate apoptosis and modulate NFκB signaling which drives the expression of genes involved in immune and inflammatory responses. In patient (pt) tumors, Debio 1143 increased PD-1/PD-L1 expression and tumor infiltrating lymphocytes. In pre-clinical models, it synergizes in vitro and in vivo with PD1/PD-L1 checkpoint inhibitors (CPIs). Methods: In a phase I study, using a mCRM model, avelumab (10 mg/kg i.v. on D1&15 q4w) was combined with escalating doses of Debio 1143 (100 mg/d to 250 mg/d orally, D1-10 & D15-24 q4w) to define the RP2D. Consenting adult pts with advanced solid tumors, normal organ function, and PS-ECOG = 0-1 were eligible provided none received prior CPI. Dose-limiting toxicities (DLTs), efficacy, safety, PK, PD and biomarkers were assessed. Results: As of DEC’18, 16 pts were treated; M/F: 8/8; ECOG = 0 in 6 (38%); median age = 58 (28-79); 5 pts had NSCLC, 2 MPM, 2 ovarian and 7 had other tumors (n = 1 each). Common AEs were: nausea (69%); fatigue (62%); vomiting (50%); cough, dyspnea, myalgia (44% each); diarrhea, anorexia (38% each); pruritus and constipation (31% each). These were generally grade 1-2, occasionally grade 3. One pt had a DLT at 250 mg/d dose: a grade 3 AST/ALT increase. No treatment-related AEs grade 4 or higher occurred. No dose-relationships for laboratory abnormalities were observed, except for ALT/AST increases, which at 200 mg/d were all grade 1 and asymptomatic. Maximal tolerated dose was not reached and there were no dose reductions. In 15 evaluable pts, 1 PR (NSCLC) and 5 SD (RECIST v1.1) were observed. Tumor shrinkage > 15% was seen in 2 other NSCLC pts. PK showed high interpatient variability and dose-proportional increase. TNFα and IFNγ peaked in plasma following Debio 1143 dose on D1 after 8 hrs, and on D17/22, in a dose-proportional manner. Four pts developed anti-avelumab antibodies. Conclusions: Debio 1143 at 200 mg/d can be safely combined with avelumab. Toxicity was predictable and mild. Clinical activity was observed in NSCLC pts. PK was linear; no drug interaction was suspected. PD and biomarker analysis is ongoing. Expansion at this RP2D is ongoing in NSCLC. Clinical trial information: NCT03270176.

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