Targeting telomerase with radiolabeled inhibitors

The expression of telomerase in approximately 85% of cancers and its absence in the majority of normal cells makes it an attractive target for cancer therapy. However the lag period between initiation of telomerase inhibition and growth arrest makes direct inhibition alone an insufficient method of treatment. However, telomerase inhibition has been shown to enhance cancer cell radiosensitivity. To investigate the strategy of simultaneously inhibiting telomerase while delivering targeted radionuclide therapy to cancer cells, 123I-radiolabeled inhibitors of telomerase were synthesized and their effects on cancer cell survival studied. An 123I-labeled analogue of the telomerase inhibitor MST-312 inhibited telomerase with an IC50 of 1.58 μM (MST-312 IC50: 0.23 μM). Clonogenic assays showed a dose dependant effect of 123I-MST-312 on cell survival in a telomerase positive cell line, MDA-MB-435

Copper-Catalyzed Synthesis of Trifluoroethylarenes from Benzylic Bromodifluoroacetates

Trifluoroethylarenes are found in a variety of biologically active molecules, and strategies for accessing this substructure are important for developing therapeutic candidates and biological probes. Trifluoroethylarenes can be directly accessed via nucleophilic trifluoromethylation of benzylic electrophiles; however, current catalytic methods do not effectively transform electron-deficient substrates and heterocycles. To address this gap, we report a Cu-catalyzed decarboxylative trifluoromethylation of benzylic bromodifluoroacetates. To account for the tolerance of sensitive functional groups, we propose an inner-sphere mechanism of decarboxylation

Neutrino suppression and extra dimensions: a minimal model

We study flavour neutrinos confined to our 4-dimensional world coupled to one "bulk" state, i.e. a Kaluza-Klein tower. We discuss the spatial development of the neutrino disappearance, the possibility of resurgence and the effective flavour transitions induced in this mechanism. We show that even a simple model can produce an energy-independent suppression at large distances, and relate this to experimental data.Comment: 14 pages, 8 figures; the exclusion of sterile neutrinos by SuperKamiokande is discussed; references adde

Anomalies and Fermion Content of Grand Unified Theories in Extra Dimensions

The restrictions imposed by anomaly cancellation on the chiral fermion content of nonsupersymmetric gauge theories based on various groups are studied in spacetime dimension D=6, 8, and 10. In particular, we show that the only mathematically consistent chiral SU(5) theory in D=6 contains three nonidentical generations.Comment: 15 pages, revtex. v2: references added to match published versio

A multi-modal video analysis approach for car park fire detection

In this paper a novel multi-modal flame and smoke detector is proposed for the detection of fire in large open spaces such as car parks. The flame detector is based on the visual and amplitude image of a time-of-flight camera. Using this multi-modal information, flames can be detected very accurately by visual flame feature analysis and amplitude disorder detection. In order to detect the low-cost flame related features, moving objects in visual images are analyzed over time. If an object possesses high probability for each of the flame characteristics, it is labeled as candidate flame region. Simultaneously, the amplitude disorder is also investigated. Also labeled as candidate flame regions are regions with high accumulative amplitude differences and high values in all detail images of the amplitude image's discrete wavelet transform. Finally, when there is overlap of at least one of the visual and amplitude candidate flame regions, fire alarm is raised. The smoke detector, on the other hand, focuses on global changes in the depth images of the time-of-flight camera, which do not have significant impact on the amplitude images. It was found that this behavior is unique for smoke. Experiments show that the proposed detectors improve the accuracy of fire detection in car parks. The flame detector has an average flame detection rate of 93%, with hardly any false positive detection, and the smoke detection rate of the TOF based smoke detector is 88%. © 2012 Elsevier Ltd

Radiofluorination of a highly potent ATM inhibitor as a potential PET imaging agent

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.Supplementary Information is available online at: https://ejnmmires.springeropen.com/articles/10.1186/s13550-022-00920-z#Sec11 .Purpose: Ataxia telangiectasia mutated (ATM) is a key mediator of the DNA damage response, and several ATM inhibitors (ATMi) are currently undergoing early phase clinical trials for the treatment of cancer. A radiolabelled ATMi to determine drug pharmacokinetics could assist patient selection in a move towards more personalised medicine. The aim of this study was to synthesise and investigate the first 18F-labelled ATM inhibitor [18F]1 for non-invasive imaging of ATM protein and ATMi pharmacokinetics. Methods: Radiofluorination of a confirmed selective ATM inhibitor (1) was achieved through substitution of a nitro-precursor with [18F]fluoride. Uptake of [18F]1 was assessed in vitro in H1299 lung cancer cells stably transfected with shRNA to reduce expression of ATM. Blocking studies using several non-radioactive ATM inhibitors assessed binding specificity to ATM. In vivo biodistribution studies were performed in wild-type and ATM-knockout C57BL/6 mice using PET/CT and ex vivo analysis. Uptake of [18F]1 in H1299 tumour xenografts was assessed in BALB/c nu/nu mice. Results: Nitro-precursor 2 was synthesised with an overall yield of 12%. Radiofluorination of 2 achieved radiochemically pure [18F]1 in 80 ± 13 min with a radiochemical yield of 20 ± 13% (decay-corrected) and molar activities up to 79.5 GBq/μmol (n = 11). In vitro, cell-associated activity of [18F]1 increased over 1 h, and retention of [18F]1 dropped to 50% over 2 h. [18F]1 uptake did not correlate with ATM expression, but could be reduced significantly with an excess of known ATM inhibitors, demonstrating specific binding of [18F]1 to ATM. In vivo, fast hepatobiliary clearance was observed with tumour uptake ranging 0.13–0.90%ID/g after 1 h. Conclusion: Here, we report the first radiofluorination of an ATM inhibitor and its in vitro and in vivo biological evaluations, revealing the benefits but also some limitations of 18F-labelled ATM inhibitors.This research was supported by MRC (MR/R01695X/1) and CRUK though the Oxford Institute for Radiation Oncology

Correlation between molar activity, injection mass and uptake of the PARP targeting radiotracer [18F]olaparib in mouse models of glioma

Supplementary information is available online at: https://ejnmmires.springeropen.com/articles/10.1186/s13550-022-00940-9#Sec15 .Purpose: Radiopharmaceuticals targeting poly(ADP-ribose) polymerase (PARP) have emerged as promising agents for cancer diagnosis and therapy. PARP enzymes are expressed in both cancerous and normal tissue. Hence, the injected mass, molar activity and potential pharmacological effects are important considerations for the use of radiolabelled PARP inhibitors for diagnostic and radionuclide therapeutic applications. Here, we performed a systematic evaluation by varying the molar activity of [18F]olaparib and the injected mass of [TotalF]olaparib to investigate the effects on tumour and normal tissue uptake in two subcutaneous human glioblastoma xenograft models. Methods: [18F]Olaparib uptake was evaluated in the human glioblastoma models: in vitro on U251MG and U87MG cell lines, and in vivo on tumour xenograft-bearing mice, after administration of [TotalF]olaparib (varying injected mass: 0.04–8.0 µg, and molar activity: 1–320 GBq/μmol). Results: Selective uptake of [18F]olaparib was demonstrated in both models. Tumour uptake was found to be dependent on the injected mass of [TotalF]olaparib (µg) but not the molar activity. An injected mass of 1 μg resulted in the highest tumour uptake (up to 6.9 ± 1.3%ID/g), independent of the molar activity. In comparison, both the lower and higher injected masses of [TotalF]olaparib resulted in lower relative tumour uptake (%ID/g; P 18F]olaparib intratumoural uptake correlated with PARP1 expression. Substantial upregulation of PARP1-3 expression was observed after administration of [TotalF]olaparib (> 0.5 µg). Conclusion: Our findings show that the injected mass of [TotalF]olaparib has significant effects on tumour uptake. Moderate injected masses of PARP inhibitor-derived radiopharmaceuticals may lead to improved relative tumour uptake and tumour-to-background ratio for cancer diagnosis and radionuclide therapy.Pancreatic Cancer U.K.; the Pancreatic Cancer Research Fund; CRUK through the Oxford Institute for Radiation Oncology, the CRUK Oxford Centre, and the CRUK/EPSRC Imaging Centre in Oxford; the EPSRC (EP/L025604/1, NS/A000024/1); and CRUK C5255/A16466

The My Active and Healthy Aging (My-AHA) ICT platform to detect and prevent frailty in older adults: Randomized control trial design and protocol

[EN] Introduction Frailty increases the risk of poor health outcomes, disability, hospitalization, and death in older adults and affects 7%¿12% of the aging population. Secondary impacts of frailty on psychological health and socialization are significant negative contributors to poor outcomes for frail older adults. Method The My Active and Healthy Aging (My-AHA) consortium has developed an information and communications technology¿based platform to support active and healthy aging through early detection of prefrailty and provision of individually tailored interventions, targeting multidomain risks for frailty across physical activity, cognitive activity, diet and nutrition, sleep, and psychosocial activities. Six hundred adults aged 60 years and older will be recruited to participate in a multinational, multisite 18-month randomized controlled trial to test the efficacy of the My-AHA platform to detect prefrailty and the efficacy of individually tailored interventions to prevent development of clinical frailty in this cohort. A total of 10 centers from Italy, Germany, Austria, Spain, United Kingdom, Belgium, Sweden, Japan, South Korea, and Australia will participate in the randomized controlled trial. Results Pilot testing (Alpha Wave) of the My-AHA platform and all ancillary systems has been completed with a small group of older adults in Europe with the full randomized controlled trial scheduled to commence in 2018. Discussion The My-AHA study will expand the understanding of antecedent risk factors for clinical frailty so as to deliver targeted interventions to adults with prefrailty. Through the use of an information and communications technology platform that can connect with multiple devices within the older adult's own home, the My-AHA platform is designed to measure an individual's risk factors for frailty across multiple domains and then deliver personalized domain-specific interventions to the individual. The My-AHA platform is technology-agnostic, enabling the integration of new devices and sensor platforms as they emerge.This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 689582 and the Australian National Health and Medical Research Council (NHRMC) European Union grant scheme (1115818). M.J.S. reports personal fees from Eli Lilly (Australia) Pty Ltd and grants from Novotech Pty Ltd, outside the submitted work. All other authors report nothing to disclose.Summers, MJ.; Rainero, I.; Vercelli, AE.; Aumayr, GA.; De Rosario Martínez, H.; Mönter, M.; Kawashima, R. (2018). The My Active and Healthy Aging (My-AHA) ICT platform to detect and prevent frailty in older adults: Randomized control trial design and protocol. Alzheimer's and Dementia: Translational Research and Clinical Interventions. 4:252-262. https://doi.org/10.1016/j.trci.2018.06.004S2522624Blair, S. N. (1995). Changes in Physical Fitness and All-Cause Mortality. JAMA, 273(14), 1093. doi:10.1001/jama.1995.03520380029031Fried, L. P., Ferrucci, L., Darer, J., Williamson, J. D., & Anderson, G. (2004). Untangling the Concepts of Disability, Frailty, and Comorbidity: Implications for Improved Targeting and Care. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 59(3), M255-M263. doi:10.1093/gerona/59.3.m255Gillick, M. (2001). Guest Editorial: Pinning Down Frailty. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 56(3), M134-M135. doi:10.1093/gerona/56.3.m134Hamerman, D. (1999). Toward an Understanding of Frailty. Annals of Internal Medicine, 130(11), 945. doi:10.7326/0003-4819-130-11-199906010-00022Fried, L. P., Tangen, C. M., Walston, J., Newman, A. B., Hirsch, C., Gottdiener, J., … McBurnie, M. A. (2001). Frailty in Older Adults: Evidence for a Phenotype. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 56(3), M146-M157. doi:10.1093/gerona/56.3.m146Panza, F., Solfrizzi, V., Barulli, M. R., Santamato, A., Seripa, D., Pilotto, A., & Logroscino, G. (2015). Cognitive Frailty: A Systematic Review of Epidemiological and Neurobiological Evidence of an Age-Related Clinical Condition. Rejuvenation Research, 18(5), 389-412. doi:10.1089/rej.2014.1637Soong, J., Poots, A., Scott, S., Donald, K., Woodcock, T., Lovett, D., & Bell, D. (2015). Quantifying the prevalence of frailty in English hospitals. BMJ Open, 5(10), e008456. doi:10.1136/bmjopen-2015-008456Varadhan, R., Walston, J., Cappola, A. R., Carlson, M. C., Wand, G. S., & Fried, L. P. (2008). Higher Levels and Blunted Diurnal Variation of Cortisol in Frail Older Women. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 63(2), 190-195. doi:10.1093/gerona/63.2.190BROWN, I., RENWICK, R., & RAPHAEL, D. (1995). Frailty. International Journal of Rehabilitation Research, 18(2), 93-102. doi:10.1097/00004356-199506000-00001Buchner, D. M., & Wagner, E. H. (1992). Preventing Frail Health. Clinics in Geriatric Medicine, 8(1), 1-18. doi:10.1016/s0749-0690(18)30494-4Kojima, G., Iliffe, S., Jivraj, S., & Walters, K. (2016). Association between frailty and quality of life among community-dwelling older people: a systematic review and meta-analysis. Journal of Epidemiology and Community Health, 70(7), 716-721. doi:10.1136/jech-2015-206717Ory, M. G., Schechtman, K. B., Miller, J. P., Hadley, E. C., Fiatarone, M. A., … Province, M. A. (1993). Frailty and Injuries in Later Life: The FICSIT Trials. Journal of the American Geriatrics Society, 41(3), 283-296. doi:10.1111/j.1532-5415.1993.tb06707.xShamliyan, T., Talley, K. M. C., Ramakrishnan, R., & Kane, R. L. (2013). Association of frailty with survival: A systematic literature review. Ageing Research Reviews, 12(2), 719-736. doi:10.1016/j.arr.2012.03.001Woodhouse, K. W., & O’Mahony, M. S. (1997). Frailty and ageing. Age and Ageing, 26(4), 245-246. doi:10.1093/ageing/26.4.245CAMPBELL, A. J., & BUCHNER, D. M. (1997). Unstable disability and the fluctuations of frailty. Age and Ageing, 26(4), 315-318. doi:10.1093/ageing/26.4.315Drey, M., Pfeifer, K., Sieber, C. C., & Bauer, J. M. (2011). The Fried Frailty Criteria as Inclusion Criteria for a Randomized Controlled Trial: Personal Experience and Literature Review. Gerontology, 57(1), 11-18. doi:10.1159/000313433Albert, M. S., DeKosky, S. T., Dickson, D., Dubois, B., Feldman, H. H., Fox, N. C., … Phelps, C. H. (2011). The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia, 7(3), 270-279. doi:10.1016/j.jalz.2011.03.008Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G., & Kokmen, E. (1999). Mild Cognitive Impairment. Archives of Neurology, 56(3), 303. doi:10.1001/archneur.56.3.303Winblad, B., Palmer, K., Kivipelto, M., Jelic, V., Fratiglioni, L., Wahlund, L.-O., … Petersen, R. C. (2004). Mild cognitive impairment - beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. Journal of Internal Medicine, 256(3), 240-246. doi:10.1111/j.1365-2796.2004.01380.xDubois, B., Hampel, H., Feldman, H. H., Scheltens, P., Aisen, P., … Andrieu, S. (2016). Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Alzheimer’s & Dementia, 12(3), 292-323. doi:10.1016/j.jalz.2016.02.002Moher, D., Hopewell, S., Schulz, K. F., Montori, V., Gotzsche, P. C., Devereaux, P. J., … Altman, D. G. (2010). CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. BMJ, 340(mar23 1), c869-c869. doi:10.1136/bmj.c869Gray, L. C., Bernabei, R., Berg, K., Finne-Soveri, H., Fries, B. E., Hirdes, J. P., … Ariño-Blasco, S. (2008). Standardizing Assessment of Elderly People in Acute Care: The interRAI Acute Care Instrument. Journal of the American Geriatrics Society, 56(3), 536-541. doi:10.1111/j.1532-5415.2007.01590.xRadloff, L. S. (1977). The CES-D Scale. Applied Psychological Measurement, 1(3), 385-401. doi:10.1177/014662167700100306Guralnik, J. M., Simonsick, E. M., Ferrucci, L., Glynn, R. J., Berkman, L. F., Blazer, D. G., … Wallace, R. B. (1994). A Short Physical Performance Battery Assessing Lower Extremity Function: Association With Self-Reported Disability and Prediction of Mortality and Nursing Home Admission. Journal of Gerontology, 49(2), M85-M94. doi:10.1093/geronj/49.2.m85Powell, L. E., & Myers, A. M. (1995). The Activities-specific Balance Confidence (ABC) Scale. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 50A(1), M28-M34. doi:10.1093/gerona/50a.1.m28Kendzierski, D., & DeCarlo, K. J. (1991). Physical Activity Enjoyment Scale: Two Validation Studies. Journal of Sport and Exercise Psychology, 13(1), 50-64. doi:10.1123/jsep.13.1.50Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). «Mini-mental state». Journal of Psychiatric Research, 12(3), 189-198. doi:10.1016/0022-3956(75)90026-6Brandt, J. (1991). The hopkins verbal learning test: Development of a new memory test with six equivalent forms. Clinical Neuropsychologist, 5(2), 125-142. doi:10.1080/13854049108403297Lubben, J. E. (1988). Assessing social networks among elderly populations. Family & Community Health, 11(3), 42-52. doi:10.1097/00003727-198811000-00008Russell, D., Peplau, L. A., & Cutrona, C. E. (1980). The revised UCLA Loneliness Scale: Concurrent and discriminant validity evidence. Journal of Personality and Social Psychology, 39(3), 472-480. doi:10.1037/0022-3514.39.3.472De Vries, O. J., Peeters, G. M. E. E., Lips, P., & Deeg, D. J. H. (2013). Does frailty predict increased risk of falls and fractures? A prospective population-based study. Osteoporosis International, 24(9), 2397-2403. doi:10.1007/s00198-013-2303-zTheou, O., Stathokostas, L., Roland, K. P., Jakobi, J. M., Patterson, C., Vandervoort, A. A., & Jones, G. R. (2011). The Effectiveness of Exercise Interventions for the Management of Frailty: A Systematic Review. Journal of Aging Research, 2011, 1-19. doi:10.4061/2011/569194Cadore, E. (2014). Strength and Endurance Training Prescription in Healthy and Frail Elderly. Aging and Disease, 5(3), 183. doi:10.14336/ad.2014.0500183Cadore, E. L., Rodríguez-Mañas, L., Sinclair, A., & Izquierdo, M. (2013). Effects of Different Exercise Interventions on Risk of Falls, Gait Ability, and Balance in Physically Frail Older Adults: A Systematic Review. Rejuvenation Research, 16(2), 105-114. doi:10.1089/rej.2012.1397Gardner, M. M. (2001). Practical implementation of an exercise-based falls prevention programme. Age and Ageing, 30(1), 77-83. doi:10.1093/ageing/30.1.77Eng, J. J. (2010). Fitness and Mobility Exercise Program for Stroke. Topics in Geriatric Rehabilitation, 26(4), 310-323. doi:10.1097/tgr.0b013e3181fee736Wadlinger, H. A., & Isaacowitz, D. M. (2008). Looking happy: The experimental manipulation of a positive visual attention bias. Emotion, 8(1), 121-126. doi:10.1037/1528-3542.8.1.121MacLeod, C. (2012). Cognitive bias modification procedures in the management of mental disorders. Current Opinion in Psychiatry, 25(2), 114-120. doi:10.1097/yco.0b013e32834fda4aMensink, R. P., & Katan, M. B. (1989). Effect of a Diet Enriched with Monounsaturated or Polyunsaturated Fatty Acids on Levels of Low-Density and High-Density Lipoprotein Cholesterol in Healthy Women and Men. New England Journal of Medicine, 321(7), 436-441. doi:10.1056/nejm19890817321070

Heparan Sulfate Regrowth Profiles Under Laminar Shear Flow Following Enzymatic Degradation

The local hemodynamic shear stress waveforms present in an artery dictate the endothelial cell phenotype. The observed decrease of the apical glycocalyx layer on the endothelium in atheroprone regions of the circulation suggests that the glycocalyx may have a central role in determining atherosclerotic plaque formation. However, the kinetics for the cells’ ability to adapt its glycocalyx to the environment have not been quantitatively resolved. Here we report that the heparan sulfate component of the glycocalyx of HUVECs increases by 1.4-fold following the onset of high shear stress, compared to static cultured cells, with a time constant of 19 h. Cell morphology experiments show that 12 h are required for the cells to elongate, but only after 36 h have the cells reached maximal alignment to the flow vector. Our findings demonstrate that following enzymatic degradation, heparan sulfate is restored to the cell surface within 12 h under flow whereas the time required is 20 h under static conditions. We also propose a model describing the contribution of endocytosis and exocytosis to apical heparan sulfate expression. The change in HS regrowth kinetics from static to high-shear EC phenotype implies a differential in the rate of endocytic and exocytic membrane turnover.National Heart, Lung, and Blood Institute (Grant HL090856-01)Singapore-MIT Allianc