CVM-1118 (foslinanib), a 2-phenyl-4-quinolone derivative, promotes apoptosis and inhibits vasculogenic mimicry via targeting TRAP1

CVM-1118 (foslinanib) is a phosphoric ester compound selected from 2-phenyl-4-quinolone derivatives. The NCI 60 cancer panel screening showed CVM-1125, the major active metabolite of CVM-1118, to exhibit growth inhibitory and cytotoxic effects at nanomolar range. CVM-1118 possesses multiple bioactivities, including inducing cellular apoptosis, cell cycle arrest at G2/M, as well as inhibiting vasculogenic mimicry (VM) formation. The TNF receptor associated protein 1 (TRAP1) was identified as the binding target of CVM-1125 using nematic protein organization technique (NPOT) interactome analysis. Further studies demonstrated CVM-1125 reduced the protein level of TRAP1 and impeded its downstream signaling by reduction of cellular succinate levels and destabilization of HIF-1α. The pharmacogenomic biomarkers associated with CVM-1118 were also examined by Whole Genome CRISPR Knock-Out Screening. Two hits (STK11 and NF2) were confirmed with higher sensitivity to the drug in cell knock-down experiments. Biological assays indicate that the mechanism of action of CVM-1118 is via targeting TRAP1 to induce mitochondrial apoptosis, suppress tumor cell growth, and inhibit vasculogenic mimicry formation. Most importantly, the loss-of-function mutations of STK11 and NF2 are potential biomarkers of CVM-1118 which can be applied in the selection of cancer patients for CVM-1118 treatment. CVM-1118 is currently in its Phase 2a clinical development

(Appendix 1) Age, Ge/Si ratio, aluminium and opal contents in ODP Sites 175-1081 and 175-1084

As a result of both culture and sediment core studies, the ratio of germanium (Ge) to silicon (Si) in diatom shells has been proposed as a proxy for monitoring whole-ocean changes in seawater Ge/Si, a ratio affected by changes in continental weathering. However, because of the difficulties of extracting and cleaning diatom frustules from deep-sea sediments, only samples from highly pure diatom oozes in the Antarctic region have been previously analyzed. Here we present data on diatom Ge/Si ratios, (Ge/Si)opal, for the time interval between 3.1 and 1.9 Ma from a mid-latitude, coastal upwelling area where significant terrigenous sediment input complicated the sample processing and analyses. In general, our (Ge/Si)opal values show the same decreasing trend after 2.6 Ma than previously measured in Antarctic sediments (Shemesh et al., 1989. Paleoceanography 4, 221-231), but with a noisier background that may reflect the local imprint of proximal continental input superimposed upon global changes in the ocean reservoir. The time of initiation of large-scale North Hemisphere glaciation at ~2.6 Ma is characterized by a declining pattern of diatom Ge/Si ratios, which could have resulted from a global increase in the input of riverine Si due to enhanced silica weathering and/or equatorward (northward) intrusions of subantarctic waters enriched in silica. High (Ge/Si)opal ratios are associated with high opal contents from the same sediment samples and with warm climate as indicated by depleted benthic foraminiferal d18O values from the North and Equatorial Atlantic. Cold periods signified by enriched benthic d18O values, on the contrary, are associated with lower (Ge/Si)opal ratios. We interpret diatom Ge/Si values to reflect the prevailing weathering state on the continents, with greater chemical weathering during warm and wet periods of the Pliocene and less during cooler and drier intervals

CO-OPETITION STRATEGY FROM THE PATENT ANALYSIS PERSPECTIVE: THE CASE OF THE STENT MARKET

Information about technological innovation and its evolutionary path can be explored by patent analysis. Therefore, for those firms which are dependant on large investments and a high business performance, such as stent manufacturers, integrating patent information with business strategy is the critical issue. The competition between stent manufactures is intensifying because of increasing global volume demand and improving technological performance. From a resource-based view, adopting a co-opetition strategy is essential for firms to keep sustainable competitive advantage. Over the last decade, patent rights have become a major tool of the co-opetition strategy. This study analyzes patent data from the USPTO during 1984 to 2005 and constructs patent information indicators to verify the process of technology evolution. On these grounds, we can understand the relative technological position and technological strength of the major manufacturers in this industry and also inspect their changes of position and business scope to examine the relationship between each firm's technology strategy and business strategy.patent strategy, co-opetition strategy, stent

Test-retest reliability and minimal detectable change of the Contextual Memory Test in older adults with and without mild cognitive impairment.

BackgroundThe ability to detect one's own memory capacity and develop strategies based on daily contexts is important for daily activities. The Contextual Memory Test (CMT) assesses self-awareness, self-efficacy, self-perception/evaluation of performance, recall, and strategy use that are associated with daily contexts, and could be a potentially suitable measurement for assessing memory and meta-memory in older adults with and without cognitive impairment. Nevertheless, the test-retest reliability and minimal detectable change (MDC) remain unknown in these individuals.ObjectiveThe purpose of this study was to examine test-retest reliability and calculate MDC of the CMT in healthy older adults and those with mild cognitive impairment (MCI).MethodsEighty-three participants completed the CMT twice with a one-month interval. Test-retest reliability was examined using intraclass correlation coefficient (ICC) in all seven domains of the CMT and the recognition subtest. The standard error of measurement (SEM) and MDC were calculated. The Bland-Altman analysis was performed to evaluate the degree of agreement between measurements.ResultsThe ICC of five domains (self-awareness, self-perception/evaluation of performance, immediate/delayed/total recall) and the recognition subtest were good to excellent (ICC = 0.63-0.94) in healthy and MCI participants and the MDC% were less than 30% The ICC of the other two domains (self-efficacy and total strategy use, TSS) were low (ICC = 0.07-0.59) and the MDC% exceeded 30%. The Bland-Altman analysis showed generally better performance in the 2nd than the 1st measurement in most CMT domains.ConclusionsOur results revealed sufficient test-retest reliability and acceptable MDC in most CMT domains in healthy and MCI participants. Only the self-efficacy and TSS domains demonstrated low ICC and large MDC. Possible practice effects were found between repeated measurements. Clinicians should be cautious when evaluating self-efficacy and strategy use using the CMT in older adults. Further improvements are needed for these two domains

Test-retest reliability and minimal detectable change of the Contextual Memory Test in older adults with and without mild cognitive impairment

[[abstract]]Background: The ability to detect one's own memory capacity and develop strategies based on daily contexts is important for daily activities. The Contextual Memory Test (CMT) assesses self-awareness, self-efficacy, self-perception/evaluation of performance, recall, and strategy use that are associated with daily contexts, and could be a potentially suitable measurement for assessing memory and meta-memory in older adults with and without cognitive impairment. Nevertheless, the test-retest reliability and minimal detectable change (MDC) remain unknown in these individuals. Objective: The purpose of this study was to examine test-retest reliability and calculate MDC of the CMT in healthy older adults and those with mild cognitive impairment (MCI). Methods: Eighty-three participants completed the CMT twice with a one-month interval. Test-retest reliability was examined using intraclass correlation coefficient (ICC) in all seven domains of the CMT and the recognition subtest. The standard error of measurement (SEM) and MDC were calculated. The Bland-Altman analysis was performed to evaluate the degree of agreement between measurements. Results: The ICC of five domains (self-awareness, self-perception/evaluation of performance, immediate/delayed/total recall) and the recognition subtest were good to excellent (ICC = 0.63-0.94) in healthy and MCI participants and the MDC% were less than 30% The ICC of the other two domains (self-efficacy and total strategy use, TSS) were low (ICC = 0.07-0.59) and the MDC% exceeded 30%. The Bland-Altman analysis showed generally better performance in the 2nd than the 1st measurement in most CMT domains. Conclusions: Our results revealed sufficient test-retest reliability and acceptable MDC in most CMT domains in healthy and MCI participants. Only the self-efficacy and TSS domains demonstrated low ICC and large MDC. Possible practice effects were found between repeated measurements. Clinicians should be cautious when evaluating self-efficacy and strategy use using the CMT in older adults. Further improvements are needed for these two domains