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EO9 (Apaziquone) is a bioreductive drug that has a chequered history. It underwent clinical trial but failed to show activity in phase II clinical trials when administered i.v. Poor drug delivery to tumours caused by a combination of rapid pharmacokinetic elimination and poor penetration through avascular tissue were the major factors responsible for EO9's poor efficacy. Based upon an understanding of why EO9 failed, a further clinical trial against patients with superficial transitional cell carcinoma of the bladder was conducted. The rationale for this was that intravesical administration directly into the bladder would circumvent the drug delivery problem, and any drug reaching the blood supply would be rapidly cleared thereby reducing the risk of systemic exposure. EO9 was well tolerated, and clinical activity against marker lesions was recorded in both phase I and II clinical trials. This article charts the pharmacological history of EO9 and discusses the potential implications that 'the EO9 story' has for the development of other loco-regional therapies. [ABSTRACT FROM AUTHOR]

OBJECTIVES: First, to compare analgesic effects of breast-feeding versus pacifier use in newborn infants undergoing blood collection via heel sticks. Second, to compare analgesic effects of pacifier use with maternal holding versus nonmaternal holding. DESIGN: A prospective, randomized, controlled trial. SETTING: Normal newborn nursery at academic teaching hospital. PARTICIPANTS: Full-term breast-feeding infants scheduled for routine newborn screening blood test via heel stick (n = 96). Interventions.-Infants randomized to 3 groups for analgesia: 1) breast-feeding, 2) pacifier use while held by mothers, 3) pacifier use while held by research assistants (nonmothers). OUTCOME MEASURES: Primary outcome was crying (percent of infants who cried during the procedure and mean percent of procedure time that infants cried). Secondary outcomes were physiologic measures. RESULTS: Fewer breast-feeding infants cried than infants using a pacifier while held by nonmothers both during the procedure (69% vs 100%, P < .01) and after the procedure (28% vs 60%, P = .03). Those infants crying during the procedure cried for less time if held by their mothers either breast-feeding (33%, P < .01) or using a pacifier (45%, P = .03) than those using a pacifier while being held by nonmothers (66%). CONCLUSION: Breast-feeding is more analgesic than pacifier use with nonmaternal holding. Maternal holding with either breast-feeding or pacifier use is more analgesic than nonmaternal holding with pacifier use, suggesting that maternal holding itself has an analgesic effect. Breast-feeding and maternal holding should be considered as pain-control measures for the neonate during heel-stick procedures. [ABSTRACT FROM AUTHOR]

This paper is the second of two which together report on a 2-year research project (Davies et al. 1994) investigating the implementation and impact of introducing mentors in the Common Foundation Programme of the new scheme for preregistration nurse education. The study was commissioned by the Department of Health and undertaken on an all-Wales basis. The first paper (Phillips et al. 1996) set the scene by discussing some underlying issues to policy reforms in nurse education, then placing the study setting within the context of a changing scenario in the National Health Service. The key techniques of data collection were then outlined (interviews, diary accounts, questionnaires, observations in clinical settings). This second paper will present the key themes to emerge from the data and suggest some important issues which arise from the findings of the research, worthy of further consideration and debate. [ABSTRACT FROM AUTHOR]

This study focused on the introduction of mentors in the Common Foundation Programme of Project 2000 schemes of preregistration nurse education. The research, which was commissioned by the Department of Health Research and Development Division on behalf of the Welsh Office Nursing Division, began in February 1992 and was undertaken on an all-Wales basis. The completed report aims to provide policy makers with information relating to important issues which are central to the teaching and learning of nursing in clinical locations. This first paper discusses some background issues and gives a brief conceptual framework for considering policy reform, summarizes the research questions which emerged and describes the methods used to address them. The second paper (to appear in the next issue of the journal) will describe the key findings from the study and discuss some ensuing potential implications and considerations for all those involved in the preparation of future practitioners of nursing. [ABSTRACT FROM AUTHOR]

Faculty are challenged to find innovative ways to teach the skills for evidenced-based practice and information literacy. Librarians are natural partners with nurse educators because of their information literacy expertise. Literature shows that an experiential approach is an effective strategy for teaching undergraduate nursing research. The authors describe the development and implementation of simple research projects in an undergraduate nursing research course and the collaboration among course faculty, nursing students, and the information literacy specialist. [ABSTRACT FROM AUTHOR]

Cerium oxide based nanozymes are intensively studied due to their catalytic activity and structural flexibility. Such nanozymes have a great future potential in human therapeutics and antimicrobial activity. The structural complexity of their surfaces enables a great variety of enzyme mimetic activities. However, selection of a specific activity remains challenging, as such activities are sensitive to morphological and compositional changes as well as the physicochemical and biological environments. When delivered into biological systems, many processes occur at the surface, redefining the biological identity and activity of the nanozyme. Inorganic phosphates and phosphate-bearing molecules are some critical examples of items that can interact with cerium oxide nanozymes. Inorganic phosphates can interact directly with cerium oxide and even have a scavenging activity converting the material into cerium phosphate. Phosphate-bearing molecules can absorb on the surface of the nanozyme where phosphatase activity may occur. Given the abundance of phosphates in biological environments, cerium oxide nanozymes are strongly affected by their local concentration. Here, we discuss the interaction of cerium oxide with phosphates and phosphate-bearing molecules, providing a focussed review of the computational and experimental literature, with a focus on the surface morphology and chemistry of the nanozyme and their impact on the phosphate adsorption and phosphatase activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To report clinical and dosimetric characteristics of 5-fraction stereotactic ablative radiotherapy (SABR) using intensity modulated proton therapy (IMPT) for localized prostate cancer., Materials and Methods: All patients receiving IMPT SABR from 2017 to 2021 for localized prostate cancer at our institution were included. Five fractions were delivered every other day to the prostate +/- seminal vesicles [clinical target volume (CTV)] with 3 mm/3% robustness. A 4-field arrangement with 2 anterior oblique and 2 opposed lateral beams was used in most patients (97%), and most (99%) had a retroprostatic hydrogel spacer., Results: A total of 534 patients with low (14%), favorable intermediate (45%), unfavorable intermediate (36%), high (4.0%), or very high-risk (0.6%) disease are evaluated. Prescription dose was 36.25 Gy (31%), 38 Gy (38%), or 40 Gy (31%) was prescribed. Median volume percentage of CTV receiving at least 100% of prescription dose [V100% (%)] was 100% [interquartile range: 99.99-100]. Rectum V50% (%), V80% (%), and V90% (%) were significantly lower in patients who had spacer, with a mean difference of -9.70%, -6.59%, and -4.42%, respectively, compared to those who did not have spacer. Femoral head dose was lower with a 4-field arrangement. Mean differences in left and right femoral head V40% (%) were -6.99% and -10.74%, respectively., Conclusion: We provide a large, novel report of patients treated with IMPT SABR for localized prostate cancer. Four-field IMPT with hydrogel spacer provides significant sparing of rectum and femoral heads without compromising target coverage., Competing Interests: The authors have no conflicts to disclose., (© 2024 The Author(s).)

Purpose: Emerging data suggest that metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease, and PSMA response has been proposed as a biomarker for treatment response. Herein, we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC., Methods and Materials: We performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation who underwent PSMA-PET/computed tomography (CT) before and after (median, 6.2 months; range, 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT maximum standardized uptake value (SUV max ) was measured for all lesions, and PSMA response was defined as the percent change in SUV max of the least responsive lesion. PSMA response was both evaluated as a continuous variable and dichotomized into PSMA responders, with a complete/partial response (at least a 30% reduction in SUV max ), and PSMA nonresponders, with stable/progressive disease (less than a 30% reduction in SUV max ). PSMA response was correlated with conventional imaging-defined metastasis-free survival (MFS) via Kaplan-Meier and Cox regression analysis., Results: A total of 131 patients with 261 treated metastases were included in the analysis, with a median follow-up of 29 months (IQR, 18.5-41.3 months). After stereotactic ablative radiation, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated that PSMA response as a continuous variable was associated with a significantly worse MFS (hazard ratio = 1.003; 95% CI, 1.001-1.006; P = .016). Patients classified as PSMA responders were found to have a significantly improved median MFS of 39.9 versus 12 months ( P = .001) compared with PSMA nonresponders. Our study is limited as it is a retrospective review of a heterogenous population., Conclusions: After stereotactic ablative radiation, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting., (© 2024 The Authors.)

Background: Prostate cancer (PCa) parenchymal brain metastases are uncommon and troubling observations in the course of the disease. Our study aims to evaluate the prevalence of brain metastases among PCa patients while reporting various therapeutic modalities, clinical features, and oncological outcomes., Methods: We retrospectively identified 34 patients with parenchymal brain metastasis out of 4575 patients using a prospectively maintained database that contains clinicopathologic characteristics of PCa patients between January 2012 and December 2021. Based on the three treatment modalities used, the patients were divided into three groups: stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and systemic therapy alone. The Kaplan-Meier curve was used to calculate overall survival [OS] probability and the Cox proportional hazards regression model was used to compare between groups., Results: At the time of brain metastasis diagnosis, the median age was 66 years, the median (interquartile range [IQR]) prostate-specific antigen (PSA) was 2.2 (0.1-26.6) ng/ml and the median (IQR) months from initial PCa diagnosis to brain metastasis development was 70.8 (27.6-100.9). The median (IQR) primary Gleason score was 8 (7-9) and over a median (IQR) follow-up time of 2.2 (1.2-16.5) months, 76.5% (n = 26) of the patients died. Thirteen (38.2%) patients had solitary lesion, whereas 21 (61.8%) had ≥2 lesions. The lesions were supratentorial in 19 (55.9%) patients, infratentorial in six (17.6%), and both sides in nine (26.5%). Among all 34 patients, 10 (29.4%) were treated with SRS, seven (20.6%) with WBRT, and 17 (50%) with systemic therapy alone. OS varied greatly between the three treatment modalities (log-rank test, p = 0.049). Those who were treated with SRS and WBRT had better OS compared with patients who were treated with systemic therapy alone (hazard ratio: 0.37, 95% confidence interval: 0.16-0.86, p = 0.022)., Conclusions: In our single-institutional study, we confirmed that PCa brain metastasis is associated with poor survival outcomes and more advanced metastatic disease. Furthermore, we found that SRS and WBRT for brain metastasis in patients with recurrent PCa appear to be associated with improved OS as compared with systemic therapy alone and are likely secondary to selection bias., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)

Major advances in prostate cancer diagnosis, staging, and management have occurred over the past decade, largely due to our improved understanding of the technical aspects and clinical applications of advanced imaging, specifically magnetic resonance imaging (MRI) and prostate-cancer-specific positron emission tomography (PET). Herein, we review the established utility of these important and exciting technologies, as well as areas of controversy and uncertainty that remain important areas for future study. There is strong evidence supporting the utility of MRI in guiding initial biopsy and assessing local disease. There is debate, however, regarding how to best use the imaging modality in risk stratification, treatment planning, and assessment of biochemical failure. Prostate-cancer-specific PET is a relatively new technology that provides great value to the evaluation of newly diagnosed, treated, and recurrent prostate cancer. However, its ideal use in treatment decision making, staging, recurrence detection, and surveillance necessitates further research. Continued study of both imaging modalities will allow for an improved understanding of their best utilization in improving cancer care.

Dipodal pyridylthiazole amine ligands L 1 and L 2 both form different metallo-supramolecular self-assemblies with Zn 2+ and Cu 2+ and these are shown to be toxic and selective towards cancer cell lines in vitro. Furthermore, potency and selectivity are highly dependent upon the metal ions, ligand system and bound anion, with significant changes in chemosensitivity and selectivity dependent upon which species are employed. Importantly, significant anti-tumor activity was observed in ovo at doses that are non-toxic., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Cerium dioxide (CeO 2 ; ceria) nanoparticles (CeNPs) are promising nanozymes that show a variety of biological activity. Effective nanozymes need to retain their activity in the face of surface speciation in biological environments, and characterizing surface speciation is therefore critical to understanding and controlling the therapeutic capabilities of CeNPs. In particular, adsorbed phosphates can impact the enzymatic activity exploited to convert phosphate prodrugs into therapeutics in vivo and also define the early stages of the phosphate-scavenging processes that lead to the transformation of active CeO 2 into inactive CePO 4 . In this work, we utilize ab initio lattice-dynamics calculations to study the interaction of phosphates with the three major surfaces of ceria and to predict the infrared (IR) and Raman spectral signatures of adsorbed phosphate species. We find that phosphates adsorb strongly to CeO 2 surfaces in a range of stable binding configurations, of which 5-fold coordinated P species in a trigonal bipyramidal coordination may represent a stable intermediate in the early stages of phosphate scavenging. We find that the phosphate species show characteristic spectral fingerprints between 500 and 1500 cm -1 , whereas the bare CeO 2 surfaces show no active modes above 600 cm -1 , and the 5-fold coordinated P species in particular show potential diagnostic P-O stretching modes between 650 and 700 cm -1 in both IR and Raman spectra. This comprehensive exploration of different binding modes for phosphates on CeO 2 and the set of reference spectra provides an important step toward the experimental characterization of phosphate speciation and, ultimately, control of its impact on the performance of ceria nanozymes., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC., Results: Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside., Conclusion: Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The synthesis and characterization of 24 ruthenium(II) arene complexes of the type [( p -cym)RuCl(Fc-acac)] (where p -cym = p-cymene and Fc-acac = functionalized ferrocenyl β-diketonate ligands) are reported, including single-crystal X-ray diffraction for 21 new complexes. Chemosensitivity studies have been conducted against human pancreatic carcinoma (MIA PaCa-2), human colorectal adenocarcinoma p53 -wildtype (HCT116 p53 +/+ ) and normal human retinal epithelial cell lines (APRE-19). The most active complex, which contains a 2-furan-substituted ligand ( 4 ), is 5x more cytotoxic than the analogs 3-furan complex ( 5 ) against MIA PaCa-2. Several complexes were screened under hypoxic conditions and at shorter-time incubations, and their ability to damage DNA was determined by the comet assay. Compounds were also screened for their potential to inhibit the growth of both bacterial and fungal strains., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: Patients with high-risk prostate cancer (HRPC) have multiple accepted treatment options. Because there is no overall survival benefit of one option over another, appropriate treatment must consider patient life expectancy, quality of life, and cost., Methods: The authors compared quality-adjusted life years (QALYs) and cost effectiveness among treatment options for HRPC using a Markov model with three treatment arms: (1) external-beam radiotherapy (EBRT) delivered with 20 fractions, (2) EBRT with 23 fractions followed by low-dose-rate (LDR) brachytherapy boost, or (3) radical prostatectomy alone. An exploratory analysis considered a simultaneous integrated boost according to the FLAME trial (ClinicalTrials.gov identifier NCT01168479)., Results: Treatment strategies were compared using the incremental cost-effectiveness ratio (ICER). EBRT with LDR brachytherapy boost was a cost-effective strategy (ICER, $20,929 per QALY gained). These results were most sensitive to variations in the biochemical failure rate. However, the results still demonstrated cost effectiveness for the brachytherapy boost paradigm, regardless of any tested parameter ranges. Probabilistic sensitivity analysis demonstrated that EBRT with LDR brachytherapy was favored in 52% of 100,000 Monte Carlo iterations. In an exploratory analysis, EBRT with a simultaneous integrated boost was also a cost-effective strategy, resulting in an ICER of $62,607 per QALY gained; however, it was not cost effective compared with EBRT plus LDR brachytherapy boost., Conclusions: EBRT with LDR brachytherapy boost may be a cost-effective treatment strategy compared with EBRT alone and radical prostatectomy for HRPC, demonstrating high-value care. The current analysis suggests that a reduction in biochemical failure alone can result in cost-effective care, despite no change in overall survival., (© 2022 American Cancer Society.)

The aim of the present study was to investigate the cytotoxicity induced by an omega-3 derivative, didocosahexaenoin (Dido) on human prostate carcinoma cells and to compare the cytotoxicity to that of docosahexaenoic acid (DHA). Different carcinoma- and non-carcinoma cells were exposed to various concentrations of omega-3 compounds at varying exposure times and the cytotoxicity was measured by MTT assay. The mechanism of Dido-induced apoptosis was investigated in prostate carcinoma cells. Dido induced stronger cytotoxicity than DHA in human prostate carcinoma cells in a dose- and time-dependent manner. Dido was also more selective and potent in inducing cytotoxicity in prostate carcinoma cells than other carcinoma cell lines tested. Pre-treatment with Dido increased the level of reactive oxygen species (ROS) in prostate carcinoma cells. Pre-treatment with various antioxidants reduced the cytotoxicity induced by Dido. Pre-treatment with Dido ≥30 ​μM also induced apoptosis which was suggested to involve an externalisation of phosphatidyl serine, a significant increase in the mitochondrial membrane potential (p ​< ​0.01) and the level of activated caspase 3/7 (p ​< ​0.05) in prostate carcinoma cells. This study is the first to show that Dido induced cytotoxicity with high selectivity and higher potency than DHA in human prostate carcinoma cells. The mechanism of action is likely to involve an increase in the level of ROS, loss in the mitochondrial membrane potential as well as externalisation of phosphatidyl serine and increase in the caspase 3/7 activity. Dido may have potential to be used for the adjuvant therapy or combination therapy with conventional chemotherapeutic drugs., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Glenn Robinson reports financial support was provided by Dr Brian Whittle Ltds., (Crown Copyright © 2022 Published by Elsevier B.V.)

Alpelisib is an alpha isoform-specific phosphatidylinositol 3-kinase (PI3K) inhibitor approved for use in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative metastatic breast cancer in combination with fulvestrant. Hyperglycemia, rash, and gastrointestinal upset are the most commonly reported adverse events associated with alpelisib. Although rash is a known on-target effect of alpelisib, patients typically present with a morbilliform rash. We describe two cases of periorbital edema associated with alpelisib. We discuss the clinical findings, management, and prognosis of this unique reaction. These cases highlight the importance of early involvement of dermatology to manage adverse cutaneous events associated with alpelisib., (Copyright © 2022. Published by Elsevier Ltd.)

Bladder cancer is the 10th most common cancer worldwide. For muscle-invasive bladder cancer (MIBC), treatment includes radical cystectomy, radiotherapy, and chemotherapy; however, the outcome is generally poor. For non-muscle-invasive bladder cancer (NMIBC), tumor recurrence is common. There is an urgent need for more effective and less harmful therapeutic approaches. Here, bladder cancer cell metabolic reprogramming to rely on aerobic glycolysis (the Warburg effect) and expression of associated molecular therapeutic targets by bladder cancer cells of different stages and grades, and in freshly resected clinical tissue, is investigated. Importantly, analyses indicate that the Warburg effect is a feature of both NMIBCs and MIBCs. In two in vitro inducible epithelial-mesenchymal transition (EMT) bladder cancer models, EMT stimulation correlated with increased lactate production, the end product of aerobic glycolysis. Protein levels of lactate dehydrogenase A (LDH-A), which promotes pyruvate enzymatic reduction to lactate, were higher in most bladder cancer cell lines (compared with LDH-B, which catalyzes the reverse reaction), but the levels did not closely correlate with aerobic glycolysis rates. Although LDH-A is expressed in normal urothelial cells, LDH-A knockdown by RNAi selectively induced urothelial cancer cell apoptotic death, whereas normal cells were unaffected-identifying LDH-A as a cancer-selective therapeutic target for bladder cancers. LDH-A and other potential therapeutic targets (MCT4 and GLUT1) were expressed in patient clinical specimens; however, positive staining varied in different areas of sections and with distance from a blood vessel. This intratumoral heterogeneity has important therapeutic implications and indicates the possibility of tumor cell metabolic coupling., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The common fern, bracken ( Pteridium aquilinum ), is well known for its toxic effects on livestock due principally to the carcinogenic constituent ptaquiloside ( 1: ), although other toxins are present including the cyanogenic glycoside, prunasin ( 2: ). Here, we report an improved and relatively "green" process for the isolation of 1: and 2: from fresh bracken fronds and the evaluation of 1: for cytotoxicity against several cancer cell lines. The results indicate that 1: displays selective toxicity against cancer cells relative to noncancer retinal epithelial cells, and the improved method for the isolation of 1: is expected to facilitate further exploration of its pharmacological properties., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Oligometastatic disease was originally defined by Hellman and Weichselbaum as an intermediate-state existing between locally confined and widely disseminated malignancy, whose natural history could be positively impacted with systemic and importantly local therapies such as radiation. Currently oligometastatic prostate cancer (OPCa) is defined clinically by lesion enumeration and several subgroups exist: de novo (synchronous) oligometastatic disease present at initial diagnosis, oligorecurrent (metachronous) disease arising after definitive therapy to the prostate, and oligoprogressive disease where isolated lesions progress in a background of otherwise stable disease. In this review we highlight current knowledge and the potential future of local therapies, such as radiation to the primary prostate and metastasis-directed therapy (MDT), in the disease management of OPCa for all 3 subgroups. In addition, we examine more recent studies classifying the patterns of failure and natural history of OPCa following treatment with local therapies. Finally, while current clinical definitions of OPCa dominate, we introduce studies attempting to elucidate a more biological definition of OPCa to allow for improved selection of patients to treat with local therapies and to better inform precision combination approaches with systemic therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

One topical area of supramolecular chemistry is the binding of anionic species but despite the importance of anions in diverse cellular processes and for cancer development, anion receptors or 'binders' have received little attention as potential anti-cancer therapeutics. Here we report self-assembling trimetallic cryptands (e.g. [L 2 (Metal) 3 ] 6+ where Metal = Cu 2+ , Zn 2+ or Mn 2+ ) which can encapsulate a range of anions and which show metal-dependent differences in chemical and biological reactivities. In cell studies, both [L 2 Cu 3 ] 6+ and [L 2 Zn 3 ] 6+ complexes are highly toxic to a range of human cancer cell lines and they show significant metal-dependent selective activity towards cancer cells compared to healthy, non-cancerous cells (by up to 2000-fold). The addition of different anions to the complexes (e.g. PO 4 3 -, SO 4 2 - or PhOPO 3 2 -) further alters activity and selectivity allowing the activity to be modulated via a self-assembly process. The activity is attributed to the ability to either bind or hydrolyse phosphate esters and mechanistic studies show differential and selective inhibition of multiple kinases by both [L 2 Cu 3 ] 6+ and [L 2 Zn 3 ] 6+ complexes but via different mechanisms.

Purpose of Review: Metastases directed therapy (MDT) is an increasingly utilized modality in patients with oligometastatic prostate cancer (OMPC) recurrence. The purpose of our review is to discuss the recent literature on the safety and oncologic outcomes of this treatment approach., Recent Findings: Metastases directed therapy, in particular, stereotactic body radiation therapy (SBRT) and salvage lymph node dissection (sLND), has shown promising efficacy in patients with OMPC. Many case series report favorable outcomes with MDT as compared to hormonal deprivation therapy alone or surveillance. Of the few case series investigating the use of MDT as part of a multimodality approach in castrate-resistant OMPC, more favorable outcomes in comparison to the use of systemic treatment alone are reported., Summary: With the recent advances in imaging techniques, particularly molecular imaging, management of OMPC has progressed rapidly in the last few years. The feasibility and benefits of MDT in OMPC have been demonstrated in prospective and retrospective series. Further prospective studies investigating the role of MDT to define optimal patient subgroups and management strategies are warranted., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The synthesis and characterization of new bis(bipyridine)ruthenium(II) ferrocenyl β-diketonate complexes, [(bpy) 2 Ru(Fc-acac)][PF 6 ] (bpy=2,2'-bipyridine; Fc-acac=functionalized ferrocenyl β-diketonate ligand) are reported. Alongside clinical platinum drugs, these bimetallic ruthenium-iron complexes have been screened for their cytotoxicity against MIA PaCa-2 (human pancreatic carcinoma), HCT116 p53 +/+ (human colon carcinoma, p53-wild type) and ARPE-19 (human retinal pigment epithelial) cell lines. With the exception of one complex, the library exhibit nanomolar potency against cancerous cell lines, and their relative potencies are up to 40x, 400x and 72x more cytotoxic than cisplatin, carboplatin and oxaliplatin, respectively. Under hypoxic conditions, the complexes remain cytotoxic (sub-micromolar range), highlighting their potential in targeting hypoxic tumor regions. The Comet assay was used to determine their ability to damage DNA, and results show dose dependent damage which correlates well with the cytotoxicity results. Their potential to treat bacterial and fungal strains has been determined, and highlight complexes have selective growth inhibition of up to 87-100 % against Staphylococcus aureus and Candida albicans., (© 2020 Wiley-VCH GmbH.)

Monosaccharides are added to the hydrophilic face of a self-assembled asymmetric Fe II metallohelix, using CuAAC chemistry. The sixteen resulting architectures are water-stable and optically pure, and exhibit improved antiproliferative selectivity against colon cancer cells (HCT116 p53 +/+ ) with respect to the non-cancerous ARPE-19 cell line. While the most selective compound is a glucose-appended enantiomer, its cellular entry is not mainly glucose transporter-mediated. Glucose conjugation nevertheless increases nuclear delivery ca 2.5-fold, and a non-destructive interaction with DNA is indicated. Addition of the glucose units affects the binding orientation of the metallohelix to naked DNA, but does not substantially alter the overall affinity. In a mouse model, the glucose conjugated compound was far better tolerated, and tumour growth delays for the parent compound (2.6 d) were improved to 4.3 d; performance as good as cisplatin but with the advantage of no weight loss in the subjects., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Functionalised triazole aldehydes are used in the highly selective self-assembly of water-compatible, optically pure, low symmetry Fe(ii)- and Zn(ii)-based metallohelices. Sub-micromolar antiproliferative activity is observed against various cancerous cell lines, accompanied by excellent selectivity versus non-cancerous cells and potential for synergistic combinatorial therapy with cisplatin.

Objective: To examine the effects of 30% oral dextrose on biochemical markers of pain, adenosine triphosphate (ATP) degradation, and oxidative stress in preterm neonates experiencing a clinically required heel lance., Study Design: Utilizing a prospective study design, preterm neonates that met study criteria (n = 169) were randomized to receive either (1) 30% oral dextrose, (2) facilitated tucking, or (3) 30% oral dextrose and facilitated tucking 2 min before heel lance. Plasma markers of ATP degradation (hypoxanthine, uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured using the premature infant pain profile-revised (PIPP-R)., Results: Oral dextrose, administered alone or with facilitated tucking, did not alter plasma markers of ATP utilization and oxidative stress., Conclusion: A single dose of 30% oral dextrose, given before a clinically required heel lance, decreased signs of pain without increasing ATP utilization and oxidative stress in premature neonates.

Objective: Due to physiological and metabolic immaturity, prematurely born infants are at increased risk because of maternal separation in many neonatal intensive care units (NICUs). The stress induced from maternal-infant separation can lead to well-documented short-term physiologic instability and potentially lifelong neurological, sociological, or psychological sequelae. Based on previous studies of kangaroo mother care (KMC) that demonstrated improvement in physiologic parameters, we examined the impact of KMC on physiologic measures of stress (abdominal temperature, heart rate, oxygen saturation, perfusion index, near-infrared spectrometry), oxidative stress, and energy utilization/conservation in preterm infants., Methods: In this randomized, stratified study of premature neonates, we compared the effects on urinary concentrations of biomarkers of energy utilization and oxidative stress of 1 hr of KMC versus incubator care on Day 3 of life in intervention-group babies ( n = 26) and control-group babies ( n = 25), respectively. On Day 4, both groups received 1 hr of KMC. Urinary samples were collected 3 hr before and 3 hr after intervention/incubator care on both days. Energy utilization was assessed by measures of adenosine triphosphate (ATP) degradation (i.e., hypoxanthine, xanthine, and uric acid). Oxidative stress was assessed using urinary allantoin. Mixed-models analysis was used to assess differences in purine/allantoin., Results: Mean allantoin levels over Days 3 and 4 were significantly lower in the KMC group than in the control group ( p = .026)., Conclusions: Results provide preliminary evidence that KMC reduces neonatal oxidative stress processes and that urinary allantoin could serve as an effective noninvasive marker for future studies.

CCR4 is the sole receptor for the chemokines CCL22 and CCL17. Clinical studies of asthmatic airways have shown levels of both ligands and CCR4 + Th2 cells to be elevated, suggestive of a role in disease. Consequently, CCR4 has aroused much interest as a potential therapeutic target and an understanding of how its cell surface expression is regulated is highly desirable. To this end, receptor expression, receptor endocytosis, and chemotaxis were assessed using transfectants expressing CCR4, CCR4 + human T cell lines, and human Th2 cells polarized in vitro. CCL17 and CCL22 drove rapid endocytosis of CCR4 in a dose-dependent manner. Replenishment at the cell surface was slow and sensitive to cycloheximide, suggestive of de novo synthesis of CCR4. Constitutive CCR4 endocytosis was also observed, with the internalized CCR4 found to be significantly degraded over a 6-h incubation. Truncation of the CCR4 C-terminus by 40 amino acids had no effect on cell surface expression, but resulted in significant impairment of ligand-induced endocytosis. Consequently, migration to both CCL17 and CCL22 was significantly enhanced. In contrast, truncation of CCR4 did not impair constitutive endocytosis or degradation, suggesting the use of alternative receptor motifs in these processes. We conclude that CCR4 cell surface levels are tightly regulated, with a degradative fate for endocytosed receptor. We postulate that this strict control is desirable, given that Th2 cells recruited by CCR4 can induce the further expression of CCR4 ligands in a positive feedback loop, thereby enhancing allergic inflammation., (© 2020 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals, Inc. on behalf of Society for Leukocyte Biology.)

Bromohexitols represent a potent class of DNA-alkylating carbohydrate chemotherapeutics that has been largely ignored over the last decades due to safety concerns. The limited structure-activity relationship data available reveals significant changes in cytotoxicity with even subtle changes in stereochemistry. However, no attempts have been made to improve the therapeutic window by rational drug design or by using a prodrug approach to exploit differences between tumour physiology and healthy tissue, such as acidic extracellular pH and hypoxia. Herein, we report the photochemical synthesis of highly substituted endoperoxides as key precursors for dibromohexitol derivatives and investigate their use as microenvironment-activated prodrugs for targeting cancer cells. One endoperoxide was identified to have a marked increased activity under hypoxic and low pH conditions, indicating that endoperoxides may serve as microenvironment-activated prodrugs., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Metastatic prostate cancer remains a life-limiting disease; while we have seen significant advances in systemic approaches which form the backbone of management, no curative paradigm yet exists. Metastasis-directed therapy (MDT) with stereotactic ablative radiotherapy (SABR) has emerged as a promising complementary technique for the management of low-volume metastatic prostate cancer. Herein we will review the rationale, potential benefits, and practical considerations associated with this approach.