Relevance of aldehydes in understanding gene-drug interactions and cancer subpopulations

Aldehyde dehydrogenase (ALDH) enzymes are key for the metabolism and detoxification of aldehydes and biosynthesis of molecules critical for cellular function. ALDHs are highly expressed in stem cells and are considered reliable experimental markers of cancer initiating cells. ALDHs are key enzymes for the bioactivation of 5-nitrofurans (5-NFNs) but downstream effects of this interaction on ALDH-mediated metabolic pathways have not been characterised. 5-NFN compounds have anti-bacterial and anti-trypanosome activity driven by bacterial- and parasite-specific nitroreductases. Despite recommendation of the 5-NFN compound, nifurtimox as a World Health Organisation essential medicine, this compound produces a multitude of side effects in humans, similar to those resulting from exposure to disulfiram, a known ALDH inhibitor. The 5-NFNs, nifurtimox and nifuroxazide are both promising candidates for repurposing as neuroblastoma and melanoma anti-cancer therapeutics, respectively. Results chapter 1 of this thesis explored the hypothesis that 5-NFNs are competitive substrates for mammalian ALDH enzymes in vivo and that this interaction drives the side-effects of 5-NFNs. Recombinant enzymes, murine liver extracts, precision cut liver slices and in vivo models were utilised to explore the effects of 5-NFNs in the liver, that highly expresses ALDH enzymes. The 5-NFNs are found to act as competitive substrates for the dehydrogenase and esterase activities of acetaldehyde-detoxifying ALDH enzymes and differentially inhibit ALDH activity in mammalian liver. Additionally, the human hepatoma cell line, HepG2 was discovered to be sensitive to 5-NFNs and the addition of ALDH substrates alters sensitivity to 5-NFNs. A study to determine the effect of 5-NFN treatment on ALDH metabolic pathways indicates that circulating levels of acetaldehyde are increased in the blood of ethanol- and nitrofuran-treated Aldh1b1-/- mice. Acetaldehyde is a DNA-damaging agent and carcinogen that cells are exposed to from endogenous and exogenous sources: However, quantitation of acetaldehyde levels in plasma presents technical difficulties. With the aim of initiating set up of a short-chain aldehyde detection method that could be applied to the quantification of aldehydes in blood and cell lysates, results chapter 2 describes the development of acetaldehyde derivatisation methods coupled with comparison of Orbitrap high-resolution and triple Quadrupole mass spectrometry detection of aldehyde derivatives. Given that ALDH1A3 is expressed in cancer initiating cells and the 5-NFN, nifuroxazide targets ALDHhigh populations, the effect of ALDH1A3 expression in ALDHhigh cells in relation to the long-chain aldehyde, and main ALDH1A3 substrate, retinaldehyde was explored. Results chapter 3 explores consequences of ALDH1A3 expression through transcriptomic analysis. To investigate the importance of ALDH1A3 activity on gene expression regulation in melanoma, transcriptomes of ALDHhigh, ALDHlow and ALDH1A3null melanoma populations were compared. Comparison of ALDHhigh- and ALDHlow-expressing A375 melanoma cell populations revealed a MITFlow-neural crest stem cell-(NCSC) high transcriptional signature that is driven through retinoic acid receptor (RXRG) signalling. This signature is differentially expressed in the ALDHhigh population compared to ALDHlow and is associated with minimal residual disease in melanoma; this highlights a therapeutic opportunity for developing an anti-cancer strategy that is specific to melanoma minimal residual disease by targeting ALDHhigh populations with nifuroxazide and inhibitors of retinaldehyde/retinoic acid metabolism. Collectively, understanding the ALDH:5-NFN enzyme-drug interaction and its downstream consequences on aldehyde-metabolising pathways informs about the mechanisms of 5-NFN-induced side effects but also has potential to be exploited for chemotherapeutic targeting of the ALDH-expressing minimal residual disease population in melanoma. This highlights ALDH as an important drug target in terms of 5-NFN-induced side effects and as a therapeutically useful target for cancer therapy

Assessment of patient-physician interactions in psoriatic arthritis: national results of the ASSIST Study

Introduction An overarching principle for the management of psoriatic arthritis (PsA) is a shared decision-making process between physicians and patients. The aim of this study is to assess the patient–physician relationship in a group of patients with PsA, by using the Perceived Efficacy in Patient–Physician Interactions (PEPPI) and CollaboRATE instruments. Methods This is a cross-sectional multicenter study where consecutive patients with PsA were enrolled. For each patient, the main demographic, comorbid conditions, and clinical data were collected, including the assessment of disease activity, function, quality of life, and impact of disease. PEPPI and CollaboRATE questionnaires were used, respectively, to evaluate the patient’s perception of the patient–physician relationship and the shared decision-making process. Results A total of 81 patients with PsA were enrolled at four centers in Italy. Overall, our patients showed a high level of confidence in obtaining needed health care, with relatively high median (IQR) values of PEPPI (20; 16–23), and a good shared decision-making process, with high median (IQR) values of CollaboRATE questionnaire (7; 6–9). PEPPI and CollaboRATE scores showed a statistically significant inverse correlation with different clinical variables such as disease duration, Leeds Enthesitis Index, PsA impact of Disease, Health Assessment Questionnaire, pain, patient’s global assessment of disease activity and clinical disease activity for PsA. The presence of comorbidities did not appear to be associated with lower values of PEPPI and CollaboRATE. Conclusions In this study, few patients with PsA were at risk of suboptimal communication with their physician. This phenomenon appeared to be primarily related to higher disease activity and burden

The local Gromov-Witten theory of CP^1 and integrable hierarchies

In this paper we begin the study of the relationship between the local Gromov-Witten theory of Calabi-Yau rank two bundles over the projective line and the theory of integrable hierarchies. We first of all construct explicitly, in a large number of cases, the Hamiltonian dispersionless hierarchies that govern the full descendent genus zero theory. Our main tool is the application of Dubrovin's formalism, based on associativity equations, to the known results on the genus zero theory from local mirror symmetry and localization. The hierarchies we find are apparently new, with the exception of the resolved conifold O(-1) + O(-1) -> P1 in the equivariantly Calabi-Yau case. For this example the relevant dispersionless system turns out to be related to the long-wave limit of the Ablowitz-Ladik lattice. This identification provides us with a complete procedure to reconstruct the dispersive hierarchy which should conjecturally be related to the higher genus theory of the resolved conifold. We give a complete proof of this conjecture for genus g<=1; our methods are based on establishing, analogously to the case of KdV, a "quasi-triviality" property for the Ablowitz-Ladik hierarchy at the leading order of the dispersive expansion. We furthermore provide compelling evidence in favour of the resolved conifold/Ablowitz-Ladik correspondence at higher genus by testing it successfully in the primary sector for g=2.Comment: 30 pages; v2: an issue involving constant maps contributions is pointed out in Sec. 3.3-3.4 and is now taken into account in the proofs of Thm 1.3-1.4, whose statements are unchanged. Several typos, formulae, notational inconsistencies have been fixed. v3: typos fixed, minor textual changes, version to appear on Comm. Math. Phy

Assessment of perinatal anxiety: diagnostic accuracy of five measures

Background Anxiety in pregnancy and after giving birth (the perinatal period) is highly prevalent but under-recognised. Robust methods of assessing perinatal anxiety are essential for services to identify and treat women appropriately. Aims To determine which assessment measures are most psychometrically robust and effective at identifying women with perinatal anxiety (primary objective) and depression (secondary objective). Method We conducted a prospective longitudinal cohort study of 2243 women who completed five measures of anxiety and depression (Generalized Anxiety Disorder scale (GAD) two- and seven-item versions; Whooley questions; Clinical Outcomes in Routine Evaluation (CORE-10); and Stirling Antenatal Anxiety Scale (SAAS)) during pregnancy (15 weeks, 22 weeks and 31 weeks) and after birth (6 weeks). To assess diagnostic accuracy a sample of 403 participants completed modules of the Mini-International Neuropsychiatric Interview (MINI). Results The best diagnostic accuracy for anxiety was shown by the CORE-10 and SAAS. The best diagnostic accuracy for depression was shown by the CORE-10, SAAS and Whooley questions, although the SAAS had lower specificity. The same cut-off scores for each measure were optimal for identifying anxiety or depression (SAAS ≥9; CORE-10 ≥9; Whooley ≥1). All measures were psychometrically robust, with good internal consistency, convergent validity and unidimensional factor structure. Conclusions This study identified robust and effective methods of assessing perinatal anxiety and depression. We recommend using the CORE-10 or SAAS to assess perinatal anxiety and the CORE-10 or Whooley questions to assess depression. The GAD-2 and GAD-7 did not perform as well as other measures and optimal cut-offs were lower than currently recommended

Elliptic logarithms, diophantine approximation and the Birch and Swinnerton-Dyer conjecture

Most, if not all, unconditional results towards the abc-conjecture rely ultimately on classical Baker's method. In this article, we turn our attention to its elliptic analogue. Using the elliptic Baker's method, we have recently obtained a new upper bound for the height of the S-integral points on an elliptic curve. This bound depends on some parameters related to the Mordell-Weil group of the curve. We deduce here a bound relying on the conjecture of Birch and Swinnerton-Dyer, involving classical, more manageable quantities. We then study which abc-type inequality over number fields could be derived from this elliptic approach.Comment: 20 pages. Some changes, the most important being on Conjecture 3.2, three references added ([Mas75], [MB90] and [Yu94]) and one reference updated [BS12]. Accepted in Bull. Brazil. Mat. So

Safety and Efficacy of Bimekizumab in Patients with Psoriatic Arthritis: 2-Year Results from Two Phase 3 Studies

Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory disease requiring long-term treatment. Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated tolerability and sustained clinical efficacy for up to 1 year for patients with PsA. Here, we report the longer-‍term safety and efficacy of bimekizumab up to 2 years. Methods: BE OPTIMAL (biologic disease-modifying antirheumatic drug [bDMARD]-naïve) and BE COMPLETE (prior inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi-IR]) assessed subcutaneous bimekizumab 160 mg every 4 weeks in patients with PsA. BE OPTIMAL included a reference arm (adalimumab 40 mg every 2 weeks); patients switched to bimekizumab at week 52 with no washout between treatments. BE OPTIMAL week 52 and BE COMPLETE week 16 completers were eligible for the BE VITAL open-label extension. Efficacy outcomes are reported to week 104/100 (BE OPTIMAL/BE COMPLETE). Results: A total of 710/852 (83.3%) bDMARD-naïve and 322/400 (80.5%) TNFi-IR patients completed week 104/100. Up to 104 weeks, patients treated with bimekizumab in BE OPTIMAL and BE COMPLETE had treatment-emergent adverse event incidence rates (exposure-adjusted incidence rate/100 patient-years) of 179.9 (95% CI 166.9, 193.7) and 100.3 (89.2, ‍112.4), respectively. The proportion of patients achieving efficacy outcomes (≥ 50% improvement from baseline in American College of Rheumatology [ACR] response criteria, 100% improvement from baseline in Psorisis Area and Severity Index [PASI], minimal disease activity [MDA]) was sustained in all patients from week 52 to week 104/100. Conclusions: Bimekizumab was well tolerated for up to 2 years of treatment and no new safety signals were observed. Sustained clinical efficacy was observed up to 2 years in bDMARD-naïve and TNFi-IR patients with active PsA. Patients switching from adalimumab to bimekizumab demonstrated further improvement in skin and nail symptoms, and sustained efficacy in joint symptoms. Trial Registration: BE OPTIMAL (NCT03895203), BE COMPLETE (NCT03896581), BE VITAL (NCT04009499)