Biomarkers in Bladder Cancer Survellance

© 2021 Sugeeta, Sharma, Ng, Nayak and Vasdev. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). https://doi.org/10.3389/fsurg.2021.735868Aim: This is a narrative review with an aim to summarise and describe urinary biomarkers in the surveillance of non-muscle-invasive bladder cancer (NMIBC). It provides a summary of FDA-approved protein biomarkers along with emerging ones which utilise genetic, epigenetic and exosomal markers. We discuss the current limitations of the available assays. Background: Current guidelines advice a combination of cystoscopy, imaging, and urine cytology in diagnosis and surveillance. Although cytology has a high specificity, it is limited by low sensitivity particularly in low grade tumours. There are six FDA-approved urinary assays for diagnosis and surveillance of bladder cancer. They have shown to improve sensitivity and specificity to be used alongside cytology and cystoscopy but have a lower specificity in comparison to cytology and false positives often occur in benign conditions. Recent developments in laboratory techniques has allowed for use of markers which are RNA-, DNA-based as well as extracellular vesicles in the past decade. Methods: Using the PubMed/Medline search engines as well as Google Scholar, we performed an online search using the terms “bladder cancer,” “non-muscle invasive bladder cancer,” and “urine biomarkers” with filter for articles in English published up to May 2021. Systematic reviews and original data of clinical trials or observational studies which contributed to the development of the biomarkers were collated. Results: Biomarkers identified were divided into FDA-approved molecular biomarkers, protein biomarkers and gene-related biomarker with a table summarising the findings of each marker with the most relevant studies. The studies conducted were mainly retrospective. Due to the early stages of development, only a few prospective studies have been done for more recently developed biomarkers and limited meta-analyses are available. Therefore a detailed evaluation of these markers are still required to decide on their clinical use. Conclusion: Advancements of analytical methods in BC has driven the research towards non-invasive liquid-based biomarkers in adjunct to urine cytology. Further large prospective studies are required to determine its feasibility in a clinical setting as they are not effective when used in isolation as they have their limitation. With the ongoing pandemic, other than reduction in costs and increased accuracy, the need for biomarkers to cope with delay in cystoscopies in diagnosis and surveillance is crucial. Thus clinical trials with direct comparison is required to improve patient care.Peer reviewe

Anticancer Activity and Cisplatin Binding Ability of Bis-Quinoline and Bis-Isoquinoline Derived [Pd2L4]4+ Metallosupramolecular Cages

New bis-quinoline (Lq) and bis-isoquinoline-based (Liq) ligands have been synthesized, along with their respective homoleptic [Pd2(Lq or Liq)4]4+ cages (Cq and Ciq). The ligands and cages were characterized by 1H, 13C and diffusion ordered (DOSY) NMR spectroscopies, high resolution electrospray ionization mass spectrometry (HR-ESIMS) and in the case of the bis-quinoline cage, X-ray crystallography. The crystal structure of the Cq architecture showed that the [Pd2(Lq)4]4+ cage formed a twisted meso isomer where the [Pd(quinoline)4]2+ units at either end of the cage architecture adopt the opposite twists (left and right handed). Conversely, Density Functional Theory (DFT) calculations on the Ciq cage architecture indicated that a lantern shaped conformation, similar to what has been observed before for related [Pd2(Ltripy)4]4+ systems (where Ltripy = 2,6-bis(pyridin-3-ylethynyl)pyridine), was generated. The different cage conformations manifest different properties for the isomeric cages. The Ciq cage is able to bind, weakly in acetonitrile, the anticancer drug cisplatin whereas the Cq architecture shows no interaction with the guest under the same conditions. The kinetic robustness of the two cages in the presence of Cl− nucleophiles was also different. The Ciq cage was completely decomposed into free Liq and [Pd(Cl)4]2− within 1 h. However, the Cq cage was more long lived and was only fully decomposed after 7 h. The new ligands (Liq and Lq) and the Pd(II) cage architectures (Ciq and Cq) were assessed for their cytotoxic properties against two cancerous cell lines (A549 lung cancer and MDA-MB-231 breast cancer) and one non-cancerous cell line (HDFa skin cells). It was found that Lq and Cq were both reasonably cytotoxic (IC50S ≈ 0.5 μM) against A549, while Ciq was slightly less active (IC50 = 7.4 μM). Liq was not soluble enough to allow the IC50 to be determined against either of the two cancerous cell lines. However, none of the molecules showed any selectivity for the cancer cells, as they were all found to have similar cytotoxicities against HDFa skin cells (IC50 values ranged from 2.6 to 3.0 μM)

Quantum-chemical investigation of the structure and the antioxidant properties of α-lipoic acid and its metabolites

Quantum-chemical computations were used to investigate the structure–antioxidant parameter relationships of α-lipoic acid and its natural metabolites bisnorlipoic acid and tetranorlipoic acid in their oxidized and reduced forms. The enantiomers of lipoic and dihydrolipoic acid were optimized using the B3LYP/6-311+G(3df,2p), B3LYP/aug-cc-pVDZ and MP2(full)/6-31+G(d,p) levels of theory as isolated molecules and in the presence of water. The geometries of the metabolites and the values of their antioxidant parameters (proton affinity, bond dissociation enthalpy, adiabatic ionization potential, spin density, and the highest occupied molecular orbital energy) were calculated at the B3LYP/6-311+G(3df,2p) level of theory. The results obtained reveal similarities between these structures: a pentatomic, nonaromatic ring is present in the oxidized forms, while an unbranched aliphatic chain (as found in saturated fatty acids) is present in both the oxidized and the reduced forms. Analysis of the spin density and the highest occupied molecular orbital energy revealed that the SH groups exhibited the greatest electron-donating activities. The values obtained for the proton affinity, bond dissociation enthalpy and adiabatic ionization potential indicate that the preferred antioxidant mechanisms for α-lipoic acid and its metabolites are sequential proton loss electron transfer in polar media and hydrogen atom transfer in vacuum

Strained alkyne polymers capable of SPAAC via ring-opening metathesis polymerization

The incorporation of strained alkynes into polymers is generally achieved by employing step-growth polymerization methods or post-polymerization reactions. Here, we demonstrate that cyclopropenone-masked strained alkynes are tolerant to chain-growth ring-opening metathesis polymerization, and that, upon post-polymerization photochemical demasking with loss of CO, the strained alkyne group appended to each repeating unit can be used to prepare functional (e.g., fluorescent or redox-active) polymers from a common polymer backbone. We support our claims about polymer transformations throughout the manuscript through the inclusion of a complete set of model reactions and characterization data for analogous molecular species. The findings of this study are transferable to other polymeric systems, opening the door to the creation of libraries of multifunctional chain-growth polymers with identical polymer backbones

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy

© Springer-Verlag GmbH Germany, part of Springer Nature 2018Background: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. Patients and methods: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. Results: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the ‘CIS’ versus ‘no-CIS’ groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63–1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01–1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23–2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34–0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82–1.35; p = 0.70). Conclusion: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.Peer reviewedFinal Accepted Versio

Exploiting the labile site in dinuclear [Pd2L2]n+ metallo-cycles: multi-step control over binding affinity without alteration of core host structure

While Nature often controls supramolecular processes through regulation giving multiple levels of activity, synthetic metallosupramolecular systems have generally been binary (e.g. on/off) when they have control over molecular recognition events, and have often relied upon drastic chemical transformations or complete disassembly to enforce this control. We report here a new low symmetry ligand with a bidentate and a monodentate site (L). In combination with Pd2+, this ligand forms a [2 + 2] metallo-macrocycle, [Pd2L2L′2]n+, where L′ is the monodentate ancillary ligand that occupies the fourth and final coordination site of the metal ions. This assembly is structurally simple, but displays nuanced, multi-step binding affinity toward a neutral diplatinate guest employed for proof-of-concept. This complexity is introduced through varying the identity of L′, which can either be solvent (DMSO) or the halides chloride, bromide or iodide. The identity of L′ alters the cationic charge of the complex (neutral DMSO versus monoanionic halides) or otherwise influences the electron deficiency of the binding site of the host through varied strength of halide-ligand intra-molecular hydrogen bonding. Cycling between these different complexes was demonstrated, except for L′ = chloride which is non-reversible. This system therefore is able to interact with a platinate guest with four different graduations of affinity in response to stimuli, while still retaining the same simple core cationic structure. In addition to multi-setting binding affinity, we believe this is the first example of the use of variable intramolecular hydrogen bonding strength in switchable ancillary ligands to alter the electronic character and hence the π-π recognition characteristics of a metallosupramolecular host.DP would like to thank the ARC for a DECRA Fellowship, and the Royal Society of New Zealand for a Rutherford Postdoctoral Fellowship. BH would like to gratefully acknowledge the MBIE Catalyst Fund for a PhD scholarship. RV would like to thank the University of Otago for a PhD scholarship. The authors would like to thank the Australia National University, the University of Canterbury, the University of Otago, and the MacDiarmid Institute for additional funding. The authors acknowledge the contribution of the NeSI high performance computing facilities to the results of this research. New Zealand’s national facilities are provided by the New Zealand eScience Infrastructure and funded jointly by NeSI’s collaborator institutions and through the Ministry of Business, Innovation & Employment’s Research Infrastructure program. https://www.nesi.org.nz

Long-cavity [Pd2L4]4+ cages and designer 1,8-naphthalimide sulfonate guests: rich variation in affinity and differentiated binding stoichiometry

One of the most appealing features of [Pd2L4]4+ cages is their well-defined cavities, giving binding affinity for specific guests. If seeking to bind larger and more complex guests, an attractive strategy is to lengthen the ligand backbone and therefore the inter-palladium(II) distance and cavity length. In comparison to large hollow [PdnL2n]2n+ polyhedra, this approach retains a well-ordered cavity environment. We report here a novel ligand, 1,3-bis(4-(4-ethynylpyridine)-phenyl)-adamantane, that has a hydrophobic bis(phenyl)adamantane core and forms [Pd2L4]4+ cages with a large 19 Å inter-palladium(II) cavity length. This cage binds long designer anions: naphthalimide sulfonates at ≥15 Å in length, which consist of two distinct domains: a naphthalimide and a phenyl sulfonate. This binding derives from hydrogen bonding between the endohedral pyridyl protons of the cage and the phenyl sulfonate group, and π–hydrophobic interactions between the adamantane core and the naphthalimide unit. The strength of binding depends on the degree of electron deficiency of the naphthalimide, brought about by the nature of substituents on this moiety, with binding constants for monoanionic guests ranging from 400 to 1800 M−1. The host/guest stoichiometry was found to be 1 : 2, unless the guest possessed a second sulfonate group, and was small enough to fit end-to-end within the cavity, in which case the stoichiometry was 1 : 1, and resulted in a high binding constant (for DMSO solvent) of 6100 M−1. This work demonstrates the subtle interplay and potential between cages and guests that are both large and that both have distinct dual zones able to interact with each other, and offers a pathway to specific and tunable binding of large guests.The authors would like to thank the University of Canterbury, the Australian National University, Massey University Albany and the University of Otago for funding. DP, KP and PK would like to thank the MacDiarmid Institute for funding. DP would like to thank the Royal Society of New Zealand for a Rutherford Postdoctoral Fellowship, and the Australian Research Council for a DECRA Fellowship

Cognitive impairment and World Trade Centre-related exposures

On 11 September 2001 the World Trade Center (WTC) in New York was attacked by terrorists, causing the collapse of multiple buildings including the iconic 110-story ‘Twin Towers’. Thousands of people died that day from the collapse of the buildings, fires, falling from the buildings, falling debris, or other related accidents. Survivors of the attacks, those who worked in search and rescue during and after the buildings collapsed, and those working in recovery and clean-up operations were exposed to severe psychological stressors. Concurrently, these ‘WTC-affected’ individuals breathed and ingested a mixture of organic and particulate neurotoxins and pro-inflammogens generated as a result of the attack and building collapse. Twenty years later, researchers have documented neurocognitive and motor dysfunctions that resemble the typical features of neurodegenerative disease in some WTC responders at midlife. Cortical atrophy, which usually manifests later in life, has also been observed in this population. Evidence indicates that neurocognitive symptoms and corresponding brain atrophy are associated with both physical exposures at the WTC and chronic post-traumatic stress disorder, including regularly re-experiencing traumatic memories of the events while awake or during sleep. Despite these findings, little is understood about the long-term effects of these physical and mental exposures on the brain health of WTC-affected individuals, and the potential for neurocognitive disorders. Here, we review the existing evidence concerning neurological outcomes in WTC-affected individuals, with the aim of contextualizing this research for policymakers, researchers and clinicians and educating WTC-affected individuals and their friends and families. We conclude by providing a rationale and recommendations for monitoring the neurological health of WTC-affected individuals