tal WITHDRAWN: Structural and mechanistic studies of hydroperoxide conversions catalyzed by a CYP74 clan epoxy alcohol synthase from amphioxus (Branchiostoma floridae) [Research Articles] By www.jlr.org Published On :: 2014-03-04T09:59:12-08:00 This manuscript has been withdrawn by the Author. Full Article
tal WITHDRAWN: The Fundamental And Pathological Importance Of Oxysterol Binding Protein And Its Related Proteins [Thematic Reviews] By www.jlr.org Published On :: 2018-10-15T08:42:37-07:00 This article has been withdrawn by the authors as part of this review overlapped with the contents of Pietrangelo A and Ridgway ND. 2018. Cellular and Molecular Life Sciences. 75; 3079-98. Full Article
tal The emerging roles of the macular pigment carotenoids throughout the lifespan and in prenatal supplementation [Thematic Reviews] By www.jlr.org Published On :: 2020-07-24T07:33:25-07:00 Since the publication of the Age-Related Eye Disease Study (AREDS2) in 2013, the macular pigment carotenoids lutein and zeaxanthin have become well known to both the eye care community and the public. It is a fascinating aspect of evolution that primates have repurposed photoprotective pigments and binding proteins from plants and insects to protect and enhance visual acuity. Moreover, utilization of these plant-derived nutrients has been widely embraced for preventing vision loss from age-related macular degeneration (AMD). More recently, there has been growing awareness that these nutrients can also play a role in improving visual performance in adults. On the other hand, the potential benefits of lutein and zeaxanthin supplementation at very young ages have been underappreciated. In this review, we examine the biochemical mechanisms and supportive data for lutein and zeaxanthin supplementation throughout the lifespan, with particular emphasis on prenatal supplementation. We propose that prenatal nutritional recommendations may aim at improving maternal and infant carotenoid status. Prenatal supplementation with lutein and zeaxanthin might enhance infant visual development and performance and may even prevent retinopathy of prematurity, possibilities that should be examined in future clinical studies. Full Article
tal Mutation in the distal NPxY motif of LRP1 alleviates dietary cholesterol-induced dyslipidemia and tissue inflammation [Research Articles] By www.jlr.org Published On :: 2020-12-09T08:30:22-08:00 The LDL receptor-related protein-1 (LRP1) is highly expressed in numerous cell types, and its impairment is associated with obesity, diabetes, and fatty liver disease. However, the mechanisms linking LRP1 to metabolic disease are not completely understood. Here, we compared the metabolic phenotype of C57BL/6J wild type and LRP1 knock-in mice carrying an inactivating mutation in the distal NPxY motif after feeding a low fat (LF) diet or high fat diets with (HFHC) or without (HF) cholesterol supplementation. In response to HF feeding, both groups developed hyperglycemia, hyperinsulinemia, and hyperlipidemia, as well as increased adiposity with adipose tissue inflammation and liver steatosis. However, when animals were fed the HF diet supplemented with cholesterol, the LRP1 NPxY mutation prevents hypercholesterolemia, reduces adipose tissue and brain inflammation, and limits liver progression to steatohepatitis. Nevertheless, insulin signaling is impaired in LRP1 NPxY mutant hepatocytes and this mutation does not protect against HFHC-induced insulin resistance. The selective metabolic improvement observed in HFHC-fed LRP1 NPxY mutant mice is due to an apparent increase of hepatic LDL receptor levels, leading to an elevated rate of plasma lipoprotein clearance and lowering of plasma and hepatic cholesterol levels. The unique metabolic phenotypes displayed by LRP1 NPxY mutant mice in response to HF or HFHC diet feeding indicate an LRP1-cholesterol axis in modulating tissue inflammation. The LRP1 NPxY mutant mouse phenotype differs from phenotypes observed in mice with tissue-specific LRP1 inactivation, thus highlighting the importance of an integrative approach to evaluate how global LRP1 dysfunction contributes to metabolic disease development. Full Article
tal Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: systematic review and network meta-analysis By www.bmj.com Published On :: Monday, December 5, 2016 - 14:46 Full Article
tal ANGPTL4 inactivates lipoprotein lipase by catalyzing the irreversible unfolding of LPLs hydrolase domain [Images In Lipid Research] By www.jlr.org Published On :: 2020-09-01T00:05:14-07:00 Full Article
tal Harmonized procedures lead to comparable quantification of total oxylipins across laboratories [Research Articles] By www.jlr.org Published On :: 2020-11-01T00:05:43-07:00 Oxylipins are potent lipid mediators involved in a variety of physiological processes. Their profiling has the potential to provide a wealth of information regarding human health and disease and is a promising technology for translation into clinical applications. However, results generated by independent groups are rarely comparable, which increases the need for the implementation of internationally agreed upon protocols. We performed an interlaboratory comparison for the MS-based quantitative analysis of total oxylipins. Five independent laboratories assessed the technical variability and comparability of 133 oxylipins using a harmonized and standardized protocol, common biological materials (i.e., seven quality control plasmas), standard calibration series, and analytical methods. The quantitative analysis was based on a standard calibration series with isotopically labeled internal standards. Using the standardized protocol, the technical variance was within ±15% for 73% of oxylipins; however, most epoxy fatty acids were identified as critical analytes due to high variabilities in concentrations. The comparability of concentrations determined by the laboratories was examined using consensus value estimates and unsupervised/supervised multivariate analysis (i.e., principal component analysis and partial least squares discriminant analysis). Interlaboratory variability was limited and did not interfere with our ability to distinguish the different plasmas. Moreover, all laboratories were able to identify similar differences between plasmas. In summary, we show that by using a standardized protocol for sample preparation, low technical variability can be achieved. Harmonization of all oxylipin extraction and analysis steps led to reliable, reproducible, and comparable oxylipin concentrations in independent laboratories, allowing the generation of biologically meaningful oxylipin patterns. Full Article
tal Progression of chronic kidney disease in familial LCAT deficiency: a follow-up of the Italian cohort [Patient-Oriented and Epidemiological Research] By www.jlr.org Published On :: 2020-12-01T00:05:39-08:00 Familial LCAT deficiency (FLD) is a rare genetic disorder of HDL metabolism, caused by loss-of-function mutations in the LCAT gene and characterized by a variety of symptoms including corneal opacities and kidney failure. Renal disease represents the leading cause of morbidity and mortality in FLD cases. However, the prognosis is not known and the rate of deterioration of kidney function is variable and unpredictable from patient to patient. In this article, we present data from a follow-up of the large Italian cohort of FLD patients, who have been followed for an average of 12 years. We show that renal failure occurs at the median age of 46 years, with a median time to a second recurrence of 10 years. Additionally, we identify high plasma unesterified cholesterol level as a predicting factor for rapid deterioration of kidney function. In conclusion, this study highlights the severe consequences of FLD, underlines the need of correct early diagnosis and referral of patients to specialized centers, and highlights the urgency for effective treatments to prevent or slow renal disease in patients with LCAT deficiency. Full Article
tal Functional impact of a congenital stationary night blindness type 2 mutation depends on subunit composition of Cav1.4 Ca2+ channels [Neurobiology] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Voltage-gated Cav1 and Cav2 Ca2+ channels are comprised of a pore-forming α1 subunit (Cav1.1-1.4, Cav2.1-2.3) and auxiliary β (β1-4) and α2δ (α2δ−1−4) subunits. The properties of these channels vary with distinct combinations of Cav subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Cav subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Cav1.4 channels typical of those in human retina: Cav1.4 splice variants with or without exon 47 (Cav1.4+ex47 and Cav1.4Δex47, respectively), and the auxiliary subunits, β2X13 and α2δ-4. We find that IT caused both Cav1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits β2X13 and α2δ-4 but not in those with β2A and α2δ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Cav1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of β2X13 and α2δ-4. Our results reveal complex actions of IT in modifying the properties of Cav1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors. Full Article
tal Novel Proteome Extraction Method Illustrates a Conserved Immunological Signature of MSI-H Colorectal Tumors [Research] By www.mcponline.org Published On :: 2020-10-01T00:05:25-07:00 Using a simple, environment friendly proteome extraction (TOP), we were able to optimize the analysis of clinical samples. Using our TOP method we analyzed a clinical cohort of microsatellite stable (MSS) and unstable (MSI-H) colorectal carcinoma (CRC). We identified a tumor cell specific, STAT1-centered, immune signature expressed by the MSI-H tumor cells. We then showed that long, but not short, exposure to Interferon- induces a similar signature in vitro. We identified 10 different temporal protein expression patterns, classifying the Interferon- protein temporal regulation in CRC. Our data sheds light on the changes that tumor cells undergo under long-term immunological pressure in vivo, the importance of STAT proteins in specific biological scenarios. The data generated could help find novel clinical biomarkers and therapeutic approaches. Full Article
tal Metabolic profiling in colorectal cancer reveals signature metabolic shifts during tumorigenesis [13. Other] By www.mcponline.org Published On :: 2010-02-10T02:51:33-08:00 Colorectal cancer (CRC) arises as the consequence of progressive changes from normal epithelial cells through polyp to tumor, and thus is an useful model for studying metabolic shift. In the present study, we studied the metabolomic profiles using high analyte specific gas chromatography/mass spectrometry (GC/MS) and liquid chromatography tandem mass spectrometry (LC/MS/MS) to attain a systems-level view of the shift in metabolism in cells progressing along the path to CRC. Colonic tissues including tumor, polyps and adjacent matched normal mucosa from 26 patients with sporadic CRC from freshly isolated resections were used for this study. The metabolic profiles were obtained using GC/MS and LC/MS/MS. Our data suggest there was a distinct profile change of a wide range of metabolites from mucosa to tumor tissues. Various amino acids and lipids in the polyps and tumors were elevated, suggesting higher energy needs for increased cellular proliferation. In contrast, significant depletion of glucose and inositol in polyps revealed that glycolysis may be critical in early tumorigenesis. In addition, the accumulation of hypoxanthine and xanthine, and the decrease of uric acid concentration, suggest that the purine biosynthesis pathway could have been substituted by the salvage pathway in CRC. Further, there was a step-wise reduction of deoxycholic acid concentration from mucosa to tumors. It appears that to gain a growth advantage, cancer cells may adopt alternate metabolic pathways in tumorigenesis and this flexibility allows them to adapt and thrive in harsh environment. Full Article
tal Multiple hypothesis testing in proteomics: A strategy for experimental work [Invited] By www.mcponline.org Published On :: 2010-12-07T11:37:01-08:00 In quantitative proteomics work, the differences in expression of many separate proteins are routinely examined to test for significant differences between treatments. This leads to the multiple hypothesis testing problem: when many separate tests are performed many will be significant by chance and be false positive results. Statistical methods such as the false discovery rate (FDR) method that deal with this problem have been disseminated for more than one decade. However a survey of proteomics journals shows that such tests are not widely implemented in one commonly used technique, quantitative proteomics using two-dimensional electrophoresis (2-DE). We outline a selection of multiple hypothesis testing methods, including some that are well known and some lesser known, and present a simple strategy for their use by the experimental scientist in quantitative proteomics work generally. The strategy focuses on the desirability of simultaneous use of several different methods, the choice and emphasis dependent on research priorities and the results in hand. This approach is demonstrated using case scenarios with experimental and simulated model data. Full Article
tal Translating Divergent Environmental Stresses into a Common Proteome Response through Hik33 in a Model Cyanobacterium [Research] By www.mcponline.org Published On :: 2017-05-12T06:53:48-07:00 The histidine kinase Hik33 plays important roles in mediating cyanobacterial response to divergent types of abiotic stresses including cold, salt, high light (HL), and osmotic stresses. However, how these functions are regulated by Hik33 remains to be addressed. Using a hik33-deficient strain (hik33) of Synechocystis sp. PCC 6803 (Synechocystis) and quantitative proteomics, we found that Hik33 depletion induces differential protein expression highly similar to that induced by divergent types of stresses. This typically includes downregulation of proteins in photosynthesis and carbon assimilation that are necessary for cell propagation, and upregulation of heat shock proteins, chaperons, and proteases that are important for cell survival. This observation indicates that depletion of Hik33 alone mimics divergent types of abiotic stresses, and that Hik33 could be important for preventing abnormal stress response in the normal condition. Moreover, we found the majority of proteins of plasmid origin were significantly upregulated in hik33, though their biological significance remains to be addressed. Together, the systematically characterized Hik33-regulated cyanobacterial proteome, which is largely involved in stress responses, builds the molecular basis for Hik33 as a general regulator of stress responses. Full Article
tal N-glycomic signature of stage II colorectal cancer and its association with the tumor microenvironment [Research] By www.mcponline.org Published On :: 2020-10-20T12:35:19-07:00 The choice for adjuvant chemotherapy in stage II colorectal cancer (CRC) is controversial as many patients are cured by surgery alone and it is difficult to identify patients with high-risk of recurrence of the disease. There is a need for better stratification of this group of patients. Mass spectrometry imaging could identify patients at risk. We report here the N-glycosylation signatures of the different cell populations in a group of stage II CRC tissue samples. The cancer cells, compared to normal epithelial cells, have increased levels of sialylation and high-mannose glycans, as well as decreased levels of fucosylation and highly branched N-glycans. When looking at the interface between cancer and its microenvironment, it seems that the cancer N-glycosylation signature spreads into the surrounding stroma at the invasive front of the tumor. This finding was more outspoken in patients with a worse outcome within this sample group. Full Article
tal Plasma proteomic data can contain personally identifiable, sensitive information and incidental findings [Research] By www.mcponline.org Published On :: 2020-12-17T07:31:07-08:00 The goal of clinical proteomics is to identify, quantify, and characterize proteins in body fluids or tissue to assist diagnosis, prognosis, and treatment of patients. In this way, it is similar to more mature omics technologies, such as genomics, that are increasingly applied in biomedicine. We argue that, similar to those fields, proteomics also faces ethical issues related to the kinds of information that is inherently obtained through sample measurement, although their acquisition was not the primary purpose. Specifically, we demonstrate the potential to identify individuals both by their characteristic, individual-specific protein levels and by variant peptides reporting on coding single nucleotide polymorphisms. Furthermore, it is in the nature of blood plasma proteomics profiling that it broadly reports on the health status of an individual – beyond the disease under investigation. Finally, we show that private and potentially sensitive information, such as ethnicity and pregnancy status, can increasingly be derived from proteomics data. Although this is potentially valuable not only to the individual, but also for biomedical research, it raises ethical questions similar to the incidental findings obtained through other omics technologies. We here introduce the necessity of - and argue for the desirability for - ethical and human rights-related issues to be discussed within the proteomics community. Those thoughts are more fully developed in our accompanying manuscript. Appreciation and discussion of ethical aspects of proteomic research will allow for deeper, better-informed, more diverse, and, most importantly, wiser guidelines for clinical proteomics. Full Article
tal Proportionality in the Conduct of Hostilities: The Incidental Harm Side of the Assessment By www.chathamhouse.org Published On :: Thu, 06 Dec 2018 14:56:29 +0000 Proportionality in the Conduct of Hostilities: The Incidental Harm Side of the Assessment Research paper sysadmin 6 December 2018 Clarification of international humanitarian law is important in ensuring compliance with the rule of proportionality, but a culture of compliance within armed forces and groups is also crucial. — Members of civil right defence conduct a search and rescue operation on destroyed buildings after an airstrike was carried out over the city of Jisr al-Shughur in Idlib province in Syria, on 6 May 2018. Photo: Hadi Harrat/Anadolu Agency/Getty Images. Summary Military operations are taking place with increasing frequency in densely populated areas. Such operations result in loss of life and harm to civilians, as well as damage to civilian objects, (including infrastructure providing essential services). In order to protect civilians, it is imperative that armed forces and groups comply with the rules of international humanitarian law on the conduct of hostilities, including the rule of proportionality. The rule of proportionality prohibits attacks which may be expected to cause incidental loss of civilian life, injury to civilians, damage to civilian objects or a combination thereof, which would be excessive in relation to the concrete and direct military advantage anticipated. This research paper analyses the key steps that belligerents must take to give effect to the rule, with a particular focus on one side of proportionality assessments – the expected incidental harm. Those undertaking proportionality assessments before or during an attack must consider whether the expected harm will be caused by the attack, and whether that harm could be expected (that is, was it reasonably foreseeable). For the purpose of proportionality assessments, injury to civilians includes disease, and there is no reason in principle to exclude mental harm, even though it is currently challenging to identify and quantify it. Damage to civilian objects includes damage to elements of the natural environment. Once the incidental harm to be considered has been identified, a value or weight must be assigned to it. This is then balanced against the value or weight of the military advantage anticipated from the attack to determine whether the harm would be excessive. In the determination of whether the expected incidental harm would be excessive compared to the anticipated military advantage, ‘excessive’ is a wide but not indeterminate standard. Belligerents should develop methodologies so that those planning and deciding attacks are provided with all necessary information on expected incidental harm, and to assist them in assigning weight to the incidental harm to be considered. If it becomes apparent that the rule of proportionality will be contravened, the attack in question must be cancelled or suspended. Clarification of the law is important in ensuring compliance with the rule of proportionality, but a culture of compliance within armed forces and groups, inculcated by their leaders, is also crucial. 2018-12-10-proportionality-conduct-hostilities-incidental-harm-gillard-final (PDF) Full Article
tal AI-driven Personalization in Digital Media: Political and Societal Implications By www.chathamhouse.org Published On :: Mon, 02 Dec 2019 12:18:52 +0000 AI-driven Personalization in Digital Media: Political and Societal Implications Research paper sysadmin 2 December 2019 The fallout from disinformation and online manipulation strategies have alerted Western democracies to the novel, nuanced vulnerabilities of our information society. This paper outlines the implications of the adoption of AI by the the legacy media, as well as by the new media, focusing on personalization. — The Reuters and other news apps seen on an iPhone, 29 January 2019. Photo: Getty Images. Summary Machine learning (ML)-driven personalization is fast expanding from social media to the wider information space, encompassing legacy media, multinational conglomerates and digital-native publishers: however, this is happening within a regulatory and oversight vacuum that needs to be addressed as a matter of urgency. Mass-scale adoption of personalization in communication has serious implications for human rights, societal resilience and political security. Data protection, privacy and wrongful discrimination, as well as freedom of opinion and of expression, are some of the areas impacted by this technological transformation. Artificial intelligence (AI) and its ML subset are novel technologies that demand novel ways of approaching oversight, monitoring and analysis. Policymakers, regulators, media professionals and engineers need to be able to conceptualize issues in an interdisciplinary way that is appropriate for sociotechnical systems. Funding needs to be allocated to research into human–computer interaction in information environments, data infrastructure, technology market trends, and the broader impact of ML systems within the communication sector. Although global, high-level ethical frameworks for AI are welcome, they are no substitute for domain- and context-specific codes of ethics. Legacy media and digital-native publishers need to overhaul their editorial codes to make them fit for purpose in a digital ecosystem transformed by ML. Journalistic principles need to be reformulated and refined in the current informational context in order to efficiently inform the ML models built for personalized communication. Codes of ethics will not by themselves be enough, so current regulatory and legislative frameworks as they relate to media need to be reassessed. Media regulators need to develop their in-house capacity for thorough research and monitoring into ML systems, and – when appropriate –proportionate sanctions for actors found to be employing such systems towards malign ends. Collaboration with data protection authorities, competition authorities and national electoral commissions is paramount for preserving the integrity of elections and of a political discourse grounded on democratic principles. Upskilling senior managers and editorial teams is fundamental if media professionals are to be able to engage meaningfully and effectively with data scientists and AI engineers. 021219 AI-driven Personalization in Digital Media final WEB (PDF) Full Article
tal Polymerase {gamma} efficiently replicates through many natural template barriers but stalls at the HSP1 quadruplex [Enzymology] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Faithful replication of the mitochondrial genome is carried out by a set of key nuclear-encoded proteins. DNA polymerase γ is a core component of the mtDNA replisome and the only replicative DNA polymerase localized to mitochondria. The asynchronous mechanism of mtDNA replication predicts that the replication machinery encounters dsDNA and unique physical barriers such as structured genes, G-quadruplexes, and other obstacles. In vitro experiments here provide evidence that the polymerase γ heterotrimer is well-adapted to efficiently synthesize DNA, despite the presence of many naturally occurring roadblocks. However, we identified a specific G-quadruplex–forming sequence at the heavy-strand promoter (HSP1) that has the potential to cause significant stalling of mtDNA replication. Furthermore, this structured region of DNA corresponds to the break site for a large (3,895 bp) deletion observed in mitochondrial disease patients. The presence of this deletion in humans correlates with UV exposure, and we have found that efficiency of polymerase γ DNA synthesis is reduced after this quadruplex is exposed to UV in vitro. Full Article
tal Talks 'intensifying' between Harper, Phillies By mlb.mlb.com Published On :: Mon, 18 Feb 2019 11:26:49 EDT The Phillies have been the favorites in the Bryce Harper sweepstakes for months, and that speculation heated up over the weekend. Full Article
tal Trout on contract talks: 'I don't want to comment' By mlb.mlb.com Published On :: Mon, 18 Feb 2019 14:54:02 EDT Mike Trout and owner Arte Moreno met separately with the media on Monday, but neither would confirm that extension talks have begun between the Angels and Trout's agent, Craig Landis. Full Article
tal Healthcare comes to standstill in east Aleppo as last hospitals are destroyed By www.bmj.com Published On :: Wednesday, November 23, 2016 - 13:46 Full Article
tal Mental Health Bill promises more tailored and dignified treatment for people detained By www.bmj.com Published On :: Thursday, November 7, 2024 - 13:06 Full Article
tal Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis By www.bmj.com Published On :: Wednesday, November 23, 2016 - 23:30 Full Article
tal Africa and Europe: Cooperation on digital transitions and new technologies By www.chathamhouse.org Published On :: Thu, 12 May 2022 09:02:13 +0000 Africa and Europe: Cooperation on digital transitions and new technologies 26 May 2022 — 8:00AM TO 12:30PM Anonymous (not verified) 12 May 2022 Online The 11th Africa Day International Conference takes place under the auspices of the president of the Republic of Slovenia, HE Mr Borut Pahor, and within the framework of the Bled Strategic Forum. Slovenia’s annual high-level Africa event seeks to improve policy outcomes for citizens in Europe and Africa as a result of a mutual understanding and strengthened cooperation between the two regions. The event is co-hosted by the Ministry of Foreign Affairs of the Republic of Slovenia, the Chatham House Africa Programme and the European Commission. Expert discussions at this year’s edition will examine collaborative links between Africa and Europe in promoting responsible innovation and governance of emerging technologies, as well as the role of technology in shaping creative and cultural economies. The conference will be broadcast live on this website, on the Slovenian Ministry of Foreign Affairs website and on the Africa Programme Facebook page. 11th Africa Day International Conference Agenda (PDF) Full Article
tal Theranostic GPA33-Pretargeted Radioimmunotherapy of Human Colorectal Carcinoma with a Bivalent 177Lu-Labeled Radiohapten By jnm.snmjournals.org Published On :: 2024-10-01T04:08:08-07:00 Radiolabeled small-molecule DOTA-haptens can be combined with antitumor/anti-DOTA bispecific antibodies (BsAbs) for pretargeted radioimmunotherapy (PRIT). For optimized delivery of the theranostic - and β-emitting isotope 177Lu with DOTA-based PRIT (DOTA-PRIT), bivalent Gemini (DOTA-Bn-thiourea-PEG4-thiourea-Bn-DOTA, aka (3,6,9,12-tetraoxatetradecane-1,14-diyl)bis(DOTA-benzyl thiourea)) was developed. Methods: Gemini was synthesized by linking 2 S-2-(4-isothiocyanatobenzyl)-DOTA molecules together via a 1,14-diamino-PEG4 linker. [177Lu]Lu-Gemini was prepared with no-carrier-added 177LuCl3 to a molar-specific activity of 123 GBq/μmol and radiochemical purity of more than 99%. The specificity of BsAb-177Lu-Gemini was verified in vitro. Subsequently, we evaluated biodistribution and whole-body clearance for [177Lu]Lu-Gemini and, for comparison, our gold-standard monovalent [177Lu]Lu-S-2-(4-aminobenzyl)-DOTA ([177Lu]Lu-DOTA-Bn) in naïve (tumor-free) athymic nude mice. For our proof-of-concept system, a 3-step pretargeting approach was performed with an established DOTA-PRIT regimen (anti-GPA33/anti-DOTA IgG-scFv BsAb, a clearing agent, and [177Lu]Lu-Gemini) in mouse models. Results: Initial in vivo studies showed that [177Lu]Lu-Gemini behaved similarly to [177Lu]Lu-DOTA-Bn, with almost identical blood and whole-body clearance kinetics, as well as biodistribution and mouse kidney dosimetry. Pretargeting [177Lu]Lu-Gemini to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [177Lu]Lu-Gemini for blood, tumor, liver, spleen, and kidneys of 3.99, 455, 6.93, 5.36, and 14.0 cGy/MBq, respectively. Tumor–to–normal tissue absorbed-dose ratios (i.e., therapeutic indices [TIs]) for the blood and kidneys were 114 and 33, respectively. In addition, we demonstrate that the use of bivalent [177Lu]Lu-Gemini in DOTA-PRIT leads to improved TIs and augmented [177Lu]Lu-Gemini tumor uptake and retention in comparison to monovalent [177Lu]Lu-DOTA-Bn. Finally, we established efficacy in SW1222 tumor-bearing mice, demonstrating that a single injection of anti-GPA33 DOTA-PRIT with 44 MBq (1.2 mCi) of [177Lu]Lu-Gemini (estimated tumor-absorbed dose, 200 Gy) induced complete responses in 5 of 5 animals and a histologic cure in 2 of 5 (40%) animals. Moreover, a significant increase in survival compared with nontreated controls was noted (maximum tolerated dose not reached). Conclusion: We have developed a bivalent DOTA-radiohapten, [177Lu]Lu-Gemini, that showed improved radiopharmacology for DOTA-PRIT application. The use of bivalent [177Lu]Lu-Gemini in DOTA-PRIT, as opposed to monovalent [177Lu]Lu-DOTA-Bn, allows curative treatments with considerably less administered 177Lu activity while still achieving high TIs for both the blood (>100) and the kidneys (>30). Full Article
tal Predicting Pathologic Complete Response in Locally Advanced Rectal Cancer with [68Ga]Ga-FAPI-04 PET, [18F]FDG PET, and Contrast-Enhanced MRI: Lesion-to-Lesion Comparison with Pathology By jnm.snmjournals.org Published On :: 2024-10-01T04:08:08-07:00 Neoadjuvant therapy in patients with locally advanced rectal cancer (LARC) has achieved good pathologic complete response (pCR) rates, potentially eliminating the need for surgical intervention. This study investigated preoperative methods for predicting pCR after neoadjuvant short-course radiotherapy (SCRT) combined with immunochemotherapy. Methods: Treatment-naïve patients with histologically confirmed LARC were enrolled from February 2023 to July 2023. Before surgery, the patients received neoadjuvant SCRT followed by 2 cycles of capecitabine and oxaliplatin plus camrelizumab. 68Ga-labeled fibroblast activation protein inhibitor ([68Ga]Ga-FAPI-04) PET/MRI, [18F]FDG PET/CT, and contrast-enhanced MRI were performed before treatment initiation and before surgery in each patient. PET and MRI features and the size and number of lesions were also collected from each scan. Each parameter’s sensitivity, specificity, and diagnostic cutoff were derived via receiver-operating-characteristic curve analysis. Results: Twenty eligible patients (13 men, 7 women; mean age, 60.2 y) were enrolled and completed the entire trial, and all patients had proficient mismatch repair or microsatellite-stable LARC. A postoperative pCR was achieved in 9 patients (45.0%). In the visual evaluation, both [68Ga]Ga-FAPI-04 PET/MRI and [18F]FDG PET/CT were limited to forecasting pCR. Contrast-enhanced MRI had a low sensitivity of 55.56% to predict pCR. In the quantitative evaluation, [68Ga]Ga-FAPI-04 change in SULpeak percentage, where SULpeak is SUVpeak standardized by lean body mass, had the largest area under the curve (0.929) with high specificity (sensitivity, 77.78%; specificity, 100.0%; cutoff, 63.92%). Conclusion: [68Ga]Ga-FAPI-04 PET/MRI is a promising imaging modality for predicting pCR after SCRT combined with immunochemotherapy. The SULpeak decrease exceeding 63.92% may provide valuable guidance in selecting patients who can forgo surgery after neoadjuvant therapy. Full Article
tal Association Between CA 15-3 and 18F-FDG PET/CT Findings in Recurrent Breast Cancer Patients at a Tertiary Referral Hospital in Kenya By jnm.snmjournals.org Published On :: 2024-10-01T04:08:08-07:00 The tumor marker cancer antigen 15-3 (CA 15-3) is that most commonly used to monitor metastatic breast cancer during active therapy and surveillance for disease recurrence after treatment. The association of CA 15-3 and 18F-FDG PET/CT findings can be considered complementary, since any significant rise may indicate the presence of disease and imaging is able to map the tumor sites. Although current guidelines do not recommend the routine performance of CA 15-3 in asymptomatic patients being followed up after definitive breast cancer treatment, most oncologists perform serial assessment of the tumor markers as part of routine follow-up of patients. The aim of this study was to evaluate the correlation between CA 15-3 levels and 18F-FDG PET/CT scan findings in patients with recurrent breast cancer. Methods: This was a cross-sectional study with data collected retrospectively. Patients being evaluated for breast cancer recurrence with 18F-FDG PET/CT imaging and CA 15-3 level were included. Evaluation of the association between CA 15-3 levels and 18F-FDG PET/CT scan findings was then done. Results: In total, 154 cases were included in this study; 62 patients had recurrence (positive) on the 18F-FDG PET/CT scans, whereas 92 patients had normal (negative) findings on follow-up 18F-FDG PET/CT scans. There was an association between CA 15-3 levels and the presence or absence of recurrence on 18F-FDG PET/CT scans, with 84.4% (27/32) of patients who had elevated CA 15-3 levels having disease recurrence on 18F-FDG PET/CT and 84.4% (27/32) of patients who had elevated CA 15-3 levels having disease recurrence on 18F-FDG PET/CT as well as a correlation with the burden of metastases. Most patients with disease recurrence on 18F-FDG PET/CT, however, had normal CA 15-3 levels. Conclusion: Higher CA 15-3 levels correlate with breast cancer recurrence on 18F-FDG PET/CT as well as with burden of metastasis. Notably, CA 15-3 levels within the reference range do not exclude breast cancer disease recurrence since more than half of patients with recurrence had normal CA 15-3 levels. 18F-FDG PET/CT should therefore be considered in patients with suspected breast cancer recurrence but normal CA 15-3 levels. Full Article
tal Tesla regains $1 trillion in market capitalization in post-election surge By www.upi.com Published On :: Fri, 08 Nov 2024 12:37:28 -0500 Tesla Friday reached a $1 trillion market capitalization value for the first time since 2022 in a post-election stock rally. Full Article
tal 11 hospitalized after explosion at Louisville food-coloring factory By www.upi.com Published On :: Tue, 12 Nov 2024 20:00:56 -0500 An explosion at a food-coloring factory in Louisville, Ky., hospitalized at least 11, including two in critical condition, on Tuesday afternoon. Full Article
tal Capitals' Alex Ovechkin nets game winner vs. Predators, extends goal streak By www.upi.com Published On :: Thu, 07 Nov 2024 08:11:02 -0500 Alex Ovechkin calmly slid into the right circle and sniped a snapshot past a blinded Juuse Saros to lead the Washington Capitals to a 3-2 triumph over the Nashville Predators. Full Article
tal Four Marines remain hospitalized month after suicide bombing at Afghan airport By www.upi.com Published On :: Fri, 24 Sep 2021 12:13:49 -0400 Four U.S. Marines remain hospitalized after an attack near Hamid Karzai International Airport in Kabul, Afghanistan, last month as service members were evacuating foreign nationals and refugees. Full Article
tal SC24 Invited Talks to Spotlight HPC’s Role in AI, Quantum Computing, and Sustainability By www.hpcwire.com Published On :: Thu, 07 Nov 2024 21:46:50 +0000 ATLANTA, Nov. 7, 2024 — As the high-performance computing (HPC) community gathers in Atlanta for SC24, the world’s largest HPC conference, the event will feature presentations from thought leaders and […] The post SC24 Invited Talks to Spotlight HPC’s Role in AI, Quantum Computing, and Sustainability appeared first on HPCwire. Full Article
tal Microsoft, Quantinuum Use Hybrid Workflow to Simulate Catalyst By www.hpcwire.com Published On :: Fri, 13 Sep 2024 13:05:49 +0000 Microsoft and Quantinuum reported the ability to create 12 logical qubits on Quantinuum’s H2 trapped ion system this week and also reported using two logical qubits on an H1 system […] The post Microsoft, Quantinuum Use Hybrid Workflow to Simulate Catalyst appeared first on HPCwire. Full Article Short Takes
tal Asthma Drug Still Being Prescribed to Kids Despite Potential Mental Health Risks By www.scientificamerican.com Published On :: Fri, 19 Jan 2024 17:00:00 GMT The allergy and asthma drug montelukast, also known as Singulair, can cause psychiatric side effects—and researchers aren’t sure why Full Article Health Pharmaceuticals Mind & Brain Mental Health
tal Farmers in Crisis, Long Overlooked, Are Finally Getting Mental Health Support By www.scientificamerican.com Published On :: Thu, 15 Feb 2024 11:45:00 GMT Amid a mounting mental health crisis among farmers, experts are working to make help more accessible Full Article Agriculture Health Mind & Brain Mental Health
tal Additional case of new mpox strain detected in Britain for a total of four By www.upi.com Published On :: Wed, 06 Nov 2024 23:31:05 -0500 An additional case of a new strain of mpox has been detected in Britain, bringing the total number of infections in the country to four. Full Article
tal AFWERX Selects IntelliTwin as the Realizable Digital Thread for HPC-scale CFD By www.hpcwire.com Published On :: Tue, 05 Dec 2023 19:11:58 +0000 RUTHERFORD, N.J., Dec. 5, 2023 — Intelligent Light has announced it has been selected by AFWERX for a Direct-to-Phase II contract in the amount of $1.15 Million focused on IntelliTwin […] The post AFWERX Selects IntelliTwin as the Realizable Digital Thread for HPC-scale CFD appeared first on HPCwire. Full Article
tal Fujitsu and Carnegie Mellon University Develop AI-powered Social Digital Twin Tech with Traffic Data from Pittsburgh By www.hpcwire.com Published On :: Thu, 07 Mar 2024 21:23:29 +0000 TOKYO, March 7, 2024 — Fujitsu Limited and Carnegie Mellon University today announced the development of a new technology to visualize traffic situations, including people and vehicles, as part of […] The post Fujitsu and Carnegie Mellon University Develop AI-powered Social Digital Twin Tech with Traffic Data from Pittsburgh appeared first on HPCwire. Full Article
tal NVIDIA Announces Earth Climate Digital Twin By www.hpcwire.com Published On :: Wed, 20 Mar 2024 22:56:26 +0000 SAN JOSE, Calif., March 20, 2024 — To accelerate efforts to combat the $140 billion in economic losses due to extreme weather brought on by climate change, NVIDIA this week […] The post NVIDIA Announces Earth Climate Digital Twin appeared first on HPCwire. Full Article
tal ORNL Develops Solution to Residual Stress Challenges in 3D-Printed Metal Structures By www.hpcwire.com Published On :: Tue, 26 Mar 2024 21:42:30 +0000 March 26, 2024 — Scientists at the Department of Energy’s Oak Ridge National Laboratory have determined how to avoid costly and potentially irreparable damage to large metallic parts fabricated through […] The post ORNL Develops Solution to Residual Stress Challenges in 3D-Printed Metal Structures appeared first on HPCwire. Full Article
tal 11 hospitalized after explosion at Louisville food-coloring factory By www.upi.com Published On :: Tue, 12 Nov 2024 20:00:56 -0500 An explosion at a food-coloring factory in Louisville, Ky., hospitalized at least 11, including two in critical condition, on Tuesday afternoon. Full Article
tal Astronaut released from hospital after return from International Space Station By www.upi.com Published On :: Sat, 26 Oct 2024 16:41:44 -0400 An unnamed astronaut was released from Ascension Sacred Heart Pensacola in Florida and returned to Johnson Space Center in Houston in good health Saturday, NASA reported. Full Article
tal An Obvious Mental Sign of Vitamin D Deficiency By www.spring.org.uk Published On :: Fri, 25 Oct 2024 16:00:43 +0000 Levels are typically lower in the body through the winter months in northern latitudes. Full Article Nutrition
tal A Classic Childhood Sign Of Good Adult Mental Health By www.spring.org.uk Published On :: Tue, 05 Nov 2024 17:00:24 +0000 Children brought up like this tend to be happier as adults. Full Article Child Psychology
tal Why People Talk 50% More About The Past Than The Future (M) By www.spring.org.uk Published On :: Thu, 07 Nov 2024 18:00:24 +0000 We are so beholden to the 'arrow of time', moving us inevitably from the past into the future, that we hardly notice it. Full Article Memory subscribers-only
tal Survey: People Are Losing Hope In Mental Health Recovery (M) By www.spring.org.uk Published On :: Tue, 12 Nov 2024 18:00:13 +0000 Is people's empathy reducing towards those struggling with mental health issues? Full Article Mental Health subscribers-only
tal Capitalism broke the climate. Now it can fix it | Akshat Rathi By www.ted.com Published On :: Mon, 23 Sep 2024 14:47:55 +0000 We can blame capitalism for worsening the climate crisis, says journalist Akshat Rathi, but we can also use it to create the solutions we need for the mess we're in. He details how “climate capitalism” — the strategic use of market forces and government policies to make polluting the planet cost more than advancing climate solutions — can flip the script and actually make sustainability profitable. Full Article Higher Education
tal Everything is improvisation — including this TED Talk | Reggie Watts By www.ted.com Published On :: Wed, 02 Oct 2024 14:57:18 +0000 In this ode to improvisation, musician and comedian Reggie Watts beatboxes, raps, loops his own rhythms and reflects upon the everyday power of turning the mundane into magic. After all, he says, we're all just making it up as we go along. Full Article Higher Education
tal A hospital in the cloud bringing health care anywhere in the world | Mohamed Aburawi By www.ted.com Published On :: Tue, 15 Oct 2024 19:52:14 +0000 What if AI could help connect you with the right medical care, exactly when you need it? Health systems entrepreneur, surgeon and TED Fellow Mohamed Aburawi explores how his digital health platform, Speetar, uses AI to bridge the healthcare gap in underserved regions, like his native Libya, by connecting patients with doctors who truly understand their needs. Full Article Higher Education
tal Poetry and music that reaches across the digital void | Elle Cordova By www.ted.com Published On :: Wed, 30 Oct 2024 14:49:04 +0000 In this whimsical talk and performance, musician and comedian Elle Cordova ponders what happened before the Big Bang. She’s then joined by guitarist Toni Lindgren for the original song “Carl Sagan,” exploring social media, human connection and how we’re all just reaching out like stars in the night sky. Full Article Higher Education