{ "items": [ "\n\n
Molecular radiotherapy using 177Lu-DOTATATE is a most effective treatment for somatostatin receptor-expressing neuroendocrine tumors. Despite its frequent and successful use in the clinic, little or no radiobiologic considerations are made at the time of treatment planning or delivery. On positive uptake on octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiologic and DNA damage effects in the tumor. Here, we visualized and quantified the extent of DNA damage response after 177Lu-DOTATATE therapy using SPECT imaging with 111In-anti-\u03b3H2AX-TAT. This work was a proof-of-principle study of this in vivo noninvasive biodosimeter with \u03b2-emitting therapeutic radiopharmaceuticals. Methods: Six cell lines were exposed to external-beam radiotherapy (EBRT) or 177Lu-DOTATATE, after which the number of \u03b3H2AX foci and the clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor-positive tumor xenografts were treated with 177Lu-DOTATATE or sham-treated and coinjected with 111In-anti-\u03b3H2AX-TAT, 111In-IgG-TAT control, or vehicle. Results: Clonogenic survival after external-beam radiotherapy was cell-line-specific, indicating varying levels of intrinsic radiosensitivity. Regarding in vitro cell lines treated with 177Lu-DOTATATE, clonogenic survival decreased and \u03b3H2AX foci increased for cells expressing high levels of somatostatin receptor subtype 2. Ex vivo measurements revealed a partial correlation between 177Lu-DOTATATE uptake and \u03b3H2AX focus induction between different regions of CA20948 xenograft tumors, suggesting that different parts of the tumor may react differentially to 177Lu-DOTATATE irradiation. Conclusion:111In-anti-\u03b3H2AX-TAT allows monitoring of DNA damage after 177Lu-DOTATATE therapy and reveals heterogeneous damage responses.
\n \n\n \n \nParaSHIFT agents have shown promise in detecting chemical targets in biological systems by magnetic resonance, but few studies have used transition metal complexes for this purpose. Here we report our investigations into CoMe6trenCl (tren = tris(2-aminoethyl)amine) as a paraSHIFT agent. The paramagnetic region of the 1H NMR spectrum shows characteristic spectral profiles in the presence of fluoride, acetate, lactate and citrate in aqueous solution. These distinctive NMR shifts of each anion are maintained even in mixtures of anions.
\n \n\n \n \nDense tumors are resistant to conventional chemotherapies due to the unique tumor microenvironment characterized by hypoxic regions that promote cellular dormancy. Bioreductive drugs that are activated in response to this hypoxic environment are an attractive strategy for therapy with anticipated lower harmful side effects in normoxic healthy tissue. Cobalt bioreductive pro-drugs that selectively release toxic payloads upon reduction in hypoxic cells have shown great promise as anticancer agents. However, the bioreductive response in the tumor microenvironment must be better understood, as current techniques for monitoring bioreduction to Co(II) such as X-ray absorption near-edge structure and extended X-ray absorption fine structure provide limited information on speciation and require synchrotron radiation sources. Here, we present magnetic resonance imaging (MRI) as an accessible and powerful technique to monitor bioreduction by treating the cobalt complex as an MRI contrast agent and monitoring the change in water signal induced by reduction from diamagnetic Co(III) to paramagnetic Co(II). Cobalt pro-drugs built upon the tris(2-pyridylmethyl)amine ligand scaffold with varying charge were investigated for distribution and activity in a 3D tumor spheroid model by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and MRI. In addition, paramagnetic 1H NMR spectroscopy of spheroids enabled determination of the speciation of activated Co(II)TPAx complexes. This study demonstrates the utility of MRI and associated spectroscopy techniques for understanding bioreductive cobalt pro-drugs in the tumor microenvironment and has broader implications for monitoring paramagnetic metal-based therapies.
\n \n\n \n \nA novel, reversible redox-active MRI probe, GdNR1, has been developed for the study of redox changes associated with diseased states. This system exhibits switching in relaxivity upon reduction and oxidation of the appended nicotinimidium. Relaxivity studies and cyclic voltammetry confirmed the impressive reversibility of this system, at a biologically-relevant reduction potential. A 2.5-fold increase in relaxivity was observed upon reduction of the complex, which corresponds to a change in the number of inner-sphere water molecules, as confirmed by luminescence lifetimes of the Eu(iii) analogue and NMRD studies. This is the first example of a redox-responsive MRI probe utilising the biologically-inspired nicotinimidium redox switch. In the future this strategy could enable the non-invasive identification of hypoxic tissue and related cardiovascular disease.
\n \n\n \n \nRationale: An effective absorbed dose response relationship is yet to be established for Lutetium-177 based radionuclide therapies such as 177Lu-DOTATATE and 177Lu-PSMA. The inherent biological heterogeneity of neuroendocrine and prostate cancers may make the prospect of establishing cohort-based dose-response relationships unobtainable. Instead, an individual-based approach, monitoring the dose-response within each tumor could provide the necessary metric to monitor treatment efficacy. Methods: We developed a dual isotope SPECT imaging strategy to monitor the change over time in the relationship between 177Lu-DOTATATE and 111In-anti-\u03b3H2AX-TAT, a modified radiolabelled antibody that allows imaging of DNA double strand breaks, in mice bearing rat pancreatic cancer xenografts. The dynamics of \u03b3H2AX foci, apoptosis and senescence following exposure to 177Lu-DOTATATE was further investigated in vitro and in ex vivo tumor sections. Results: The change in slope of the 111In-anti-\u03b3H2AX-TAT to 177Lu signal between days 5 and 7 was found to be highly predictive of survival (r = 0.955, P < 0.0001). This pivotal timeframe was investigated further in vitro: clonogenic survival correlated with the number of \u03b3H2AX foci at day 6 (r = -0.995, P < 0.0005). While there was evidence of continuously low levels of apoptosis, delayed induction of senescence in vitro appeared to better account for the \u03b3H2AX response to 177Lu. The induction of senescence was further investigated by ex vivo analysis and corresponded with sustained retention of 177Lu within tumor regions. Conclusions: Dual isotope SPECT imaging can provide individualized tumor dose-responses that can be used to predict lutetium-177 treatment efficacy. This bio-dosimeter metric appears to be dependent upon the extent of senescence induction and suggests an integral role that senescence plays in lutetium-177 treatment efficacy.
\n \n\n \n \nBACKGROUND: Medical students' preparedness for clinical practice is well researched, yet little is known on the extent to which students are being prepared for a medical career. This paper reports the construction of a short medical inventory titled eXploring medical sTudents' caReer reAdiness (XTRA) to measure students' career readiness based on Super's theory of career maturity. APPROACH: We designed an instrument consisting of a series of 5-point Likert-scale to identify participants competencies regarding career exploration and planning during their undergraduate studies. The instrument was completed by 348 medical students from 41 universities in the United Kingdom. We examined the validity and reliability of the instrument through Exploratory Factor Analysis, Cronbach's coefficient \u03b1 and Pearson correlation. EVALUATION: Exploratory Factor Analysis revealed that 16 of the 20-items survey were aligned with the exploration stage of Super's theory: Crystallisation (Career goals), Specification (Career pathways) and Implementation (Career accomplishments). The four items that formed two separate statistical factors were specific to a current medical career in the UK. Internal reliability for Super's factor subscales were acceptable (\u03b1\u2009=\u20090.71 to \u03b1\u2009=\u20090.81). A significant positive relationship was found between students' overall rating of career readiness and the three factors, indicating construct validity. IMPLICATIONS: The XTRA Inventory is a short instrument with construct and content validity specifically designed to measure career readiness of medical students. Further work on its psychometric properties will help establish this inventory to be used as a guidance and career counselling tool by medical educators and educational institutions in developing career development programmes.
\n \n\n \n \nThe European Society of Organ Transplantation (ESOT) strives to promote equity, diversity, and inclusion (EDI) across all its activities. We surveyed the transplant community's experiences and perspectives regarding EDI within ESOT as an organization and its educational activities, and research in general. A total of 299 respondents completed the questionnaire. About half agreed that ESOT's Executive Committee, Council, and Sections/Committees are diverse and inclusive (51%) and that ESOT promotes EDI in its live and digital educational activities (54%). Forty percent of respondents agreed that scientific and clinical trials in the field of transplantation are diverse and inclusive. Despite the wide distribution of the survey, most of the respondents self-identified as White and were either physician or surgeon. However, the results contribute a unique insight into the experiences and perspectives of the transplantation community regarding EDI. Whilst ESOT is committed to the principles of EDI, perceptions and the high number of proposals show the apparent need to prioritize efforts to embed EDI across ESOT and transplantation science. These data should constitute a starting point for change and provide guidance for future efforts to promote EDI within the transplantation community.
\n \n\n \n \nRenal ex vivo normothermic machine perfusion (NMP) is under development as an assessment tool for high-risk kidney grafts and as a means of achieving more physiologically accurate organ preservation. On-going hemolysis has been reported during NMP, as this technique relies on red blood cells for oxygen delivery. In this study, we confirm the occurrence of progressive hemolysis during 6-hour kidney NMP. NMP-associated erythrostasis in the glomeruli and in peri-glomerular vascular networks points to an interaction between the red blood cells and the graft. Continuous hemolysis resulted in prooxidative changes in the perfusate, which could be quenched by addition of fresh frozen plasma. In a cell-based system, this hemolysis induced redox stress and exhibited toxic effects at high concentrations. These findings highlight the need for a more refined oxygen carrier in the context of renal NMP.
\n \n\n \n \nAs more data becomes available, the Banff 2007 working classification of skin-containing vascularized composite allograft (VCA) pathology is expected to evolve and develop. This report represents the Banff VCA Working Group's consensus on the first revision of the 2007 scoring system. Prior to the 2022 Banff-CST Joint Meeting, eighty-three clinicians and/or researchers were invited to a virtual meeting to discuss whether the 2007 Banff VCA system called for a revision. Unanimously, it was determined that the vascular changes were to be included in the first revision. Subsequently, two international online surveys, each followed by virtual discussions, were launched. The goals were: 1) to identify which changes define severe rejection, 2) to grade their importance in the evaluation of severe rejection, 3) to identify emerging criteria to diagnose rejection. A final hybrid (in person and virtual) discussion at the Banff/CST join meeting finalized the terminology, the definition, a scoring system, and a reporting system of the vascular changes. This proposal represents an international consensus on this topic and establishes the first revision of the Banff 2007 working classification of skin-containing vascularized composite allograft pathology.
\n \n\n \n \nThe immune system is integral to cardiovascular health and disease. Targeting inflammation ameliorates adverse cardiovascular outcomes. Atherosclerosis, a major underlying cause of cardiovascular disease, is conceptualized as lipid-driven inflammation in which macrophages play a nonredundant role. However, evidence emerging so far from single-cell atlases suggests a dichotomy between lipid-associated and inflammatory macrophage states. Here, we present an inclusive reference atlas of human intraplaque immune cell communities. Combining single-cell RNA sequencing (scRNA-seq) of human surgical carotid endarterectomies in a discovery cohort with bulk RNA-seq and immunohistochemistry in a validation cohort (the Carotid Plaque Imaging Project), we reveal the existence of PLIN2hi/TREM1hi macrophages as a Toll-like receptor (TLR)-dependent inflammatory lipid-associated macrophage state linked to cerebrovascular events. Our study shifts the current paradigm of lipid-driven inflammation by providing biological evidence for a pathogenic macrophage transition to an inflammatory lipid-associated phenotype and for its targeting as a new treatment strategy for cardiovascular disease.
\n \n\n \n \nOBJECTIVES: To evaluate the long term risks of invasive breast cancer and death related to breast cancer after non-screen detected ductal carcinoma in situ. Risks for women in the general population and for women diagnosed with ductal carcinoma in situ via the screening programme were compared. DESIGN: Population based cohort study. SETTING: Data from the National Disease Registration Service. PARTICIPANTS: All 27\u2009543 women in England who were diagnosed with ductal carcinoma in situ, outside the NHS breast screening programme, during 1990 to 2018. MAIN OUTCOME MEASURES: Incident invasive breast cancer and death caused by breast cancer. RESULTS: By 31 December 2018, 3651 women with non-screen detected ductal carcinoma in situ had developed invasive breast cancer, more than four times higher than expected from national cancer incidence rates (ratio of observed to expected rate was 4.21 (95% conference interval 4.07 to 4.35)). The ratio of observed to expected rate of developing invasive breast cancer remained increased throughout follow-up among women aged <45-70 years. The 25 year cumulative risks of invasive breast cancer by age at diagnosis of ductal carcinoma in situ were 27.3% for <45 years, 25.2% for 45-49 years, 21.7% for 50-59 years, and 20.8% for 60-70 years. 908 women died of breast cancer, almost four times higher than that expected from breast cancer death rates in the general population (ratio of observed to expected rate 3.83 (3.59 to 4.09)). The ratio of observed to expected rate of mortality attributed to breast cancer remained increased throughout follow-up. The 25 year cumulative risks of breast cancer death by age at ductal carcinoma in situ diagnosis were 7.6% for <45 years, 5.8% for 45-49 years, 5.9% for 50-59 years, and 6.2% for 60-70 years. Among women aged 50-64 years, and therefore eligible for breast screening by the NHS, the ratio of observed to expected rate of invasive breast cancer in women with non-screen detected compared with screen detected ductal carcinoma in situ was 1.26 (95% conference interval 1.17 to 1.35), while the ratio for mortality from breast cancer was 1.37 (1.17 to 1.60). Among 22\u2009753 women with unilateral ductal carcinoma in situ undergoing surgery, those who had mastectomy rather than breast conserving surgery had a lower 25 year cumulative rate of ipsilateral invasive breast cancer (mastectomy 8.2% (95% conference interval 7.0% to 9.4%), breast conserving surgery with radiotherapy 19.8% (16.2% to 23.4%), and breast conserving surgery with no radiotherapy recorded 20.6% (18.7% to 22.4%)). However, reductions did not translate into a lower 25 year cumulative rate of deaths attributable to breast cancer (mastectomy 6.5% (4.9% to 10.9%), breast conserving surgery with radiotherapy 8.6% (5.9% to 15.5%), breast conserving surgery with no radiotherapy recorded 7.8% (6.3% to 11.5%)). CONCLUSIONS: For at least 25 years after their diagnosis, women with non-screen detected ductal carcinoma in situ had higher long term risks of invasive breast cancer and breast cancer death than women in the general population. Additionally, they had higher long term risks than women with screen detected ductal carcinoma in situ. Mastectomy was associated with lower risks of invasive breast cancer than breast conserving surgery, even when accompanied by radiotherapy. However, risks of breast cancer death appeared similar for mastectomy, breast conserving surgery with radiotherapy, and breast conserving surgery with no radiotherapy recorded.
\n \n\n \n \nAim: Despite its abundance in pancreatic islets of Langerhans and proven antihyperglycemic effects, the impact of the essential amino acid, taurine, on islet \u03b2-cell biology has not yet received due consideration, which prompted the current studies exploring the molecular selectivity of taurine import into \u03b2-cells and its acute and chronic intracellular interactions. Methods: The molecular aspects of taurine transport were probed by exposing the clonal pancreatic BRIN BD11 \u03b2-cells and primary mouse and human islets to a range of the homologs of the amino acid (assayed at 2\u201320 mM), using the hormone release and imaging of intracellular signals as surrogate read-outs. Known secretagogues were employed to profile the interaction of taurine with acute and chronic intracellular signals. Results: Taurine transporter TauT was expressed in the islet \u03b2-cells, with the transport of taurine and homologs having a weak sulfonate specificity but significant sensitivity to the molecular weight of the transporter. Taurine, hypotaurine, homotaurine, and \u03b2-alanine enhanced insulin secretion in a glucose-dependent manner, an action potentiated by cytosolic Ca2+ and cAMP. Acute and chronic \u03b2-cell insulinotropic effects of taurine were highly sensitive to co-agonism with GLP-1, forskolin, tolbutamide, and membrane depolarization, with an unanticipated indifference to the activation of PKC and CCK8 receptors. Pre-culturing with GLP-1 or KATP channel inhibitors sensitized or, respectively, desensitized \u03b2-cells to the acute taurine stimulus. Conclusion: Together, these data demonstrate the pathways whereby taurine exhibits a range of beneficial effects on insulin secretion and \u03b2-cell function, consistent with the antidiabetic potential of its dietary low-dose supplementation.
\n \n\n \n \nUnderstanding prostate carcinogenesis is crucial not only for identifying new treatment targets but also for developing effective strategies to manage the asymptomatic form of the disease. There is a lack of consensus about predicting the indolent form of the disease prostate cancer, leading to uncertainties regarding treatment initiation. This review aims to enhance the assessment and management of early prostate cancer by providing a comprehensive picture of the molecular anatomy of the prostate, synthesising current evidence, highlighting knowledge gaps, and identifying future directions. It presents evidence for the efficacy of active surveillance as an alternative treatment strategy and its potential benefits in specific patient groups through androgen receptor disruption. Overall, an improved understanding of prostate carcinogenesis and its molecular underpinnings can pave the way for tailored and precise management approaches for this common cancer. Further development and validation of molecule-based assessment tools are needed. Integrating genomic, proteomic, and phenotypic models, as well as functional approaches, can help predict outcomes. This facilitates selecting candidates for active surveillance and targeting interventions for higher-risk cases, contributing to more precise management strategies.
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