NT1014, a novel biguanide, inhibits ovarian cancer growth in vitro and in vivo

Abstract Background NT1014 is a novel biguanide and AMPK activator with a high affinity for the organic cation-specific transporters, OCT1 and OCT3. We sought to determine the anti-tumorigenic effects of NT1014 in human ovarian cancer cell lines as well as in a genetically engineered mouse model of high-grade serous ovarian cancer. Methods The effects of NT1014 and metformin on cell proliferation were assessed by MTT assay using the human ovarian cancer cell lines, SKOV3 and IGROV1, as well as in primary cultures. In addition, the impact of NT1014 on cell cycle progression, apoptosis, cellular stress, adhesion, invasion, glycolysis, and AMPK activation/mTOR pathway inhibition was also explored. The effects of NT1014 treatment in vivo was evaluated using the K18 − gT121+/−; p53fl/fl; Brca1fl/fl (KpB) mouse model of high-grade serous ovarian cancer. Results NT1014 significantly inhibited cell proliferation in both ovarian cancer cell lines as well as in primary cultures. In addition, NT1014 activated AMPK, inhibited downstream targets of the mTOR pathway, induced G1 cell cycle arrest/apoptosis/cellular stress, altered glycolysis, and reduced invasion/adhesion. Similar to its anti-tumorigenic effects in vitro, NT1014 decreased ovarian cancer growth in the KpB mouse model of ovarian cancer. NT1014 appeared to be more potent than metformin in both our in vitro and in vivo studies. Conclusions NT1014 inhibited ovarian cancer cell growth in vitro and in vivo, with greater efficacy than the traditional biguanide, metformin. These results support further development of NT1014 as a useful therapeutic approach for the treatment of ovarian cancer

Gabapentin for pain management following major surgery: a placebo controlled, double blind, randomized clinical trial (The GAP Study)

Background:  Gabapentin is an anticonvulsant medication with approval for use in neuropathic pain and epileptic disorders. It is frequently added to multimodal analgesic regimens during and after surgery to reduce opioid use while controlling pain effectively. There is little evidence to show its effectiveness in major surgery. Methods:  In this multicenter, double blinded, randomized controlled trial, adults undergoing major cardiac, thoracic or abdominal surgery were randomized to receive either gabapentin (600mg before surgery, 300mg twice daily for 2 days after surgery) or placebo. The primary outcome was length of hospital stay. Secondary outcomes included acute and chronic pain, total opioid use, adverse health events and health related quality of life. Patients were followed up daily in-hospital until discharge and then at 4-weeks and 4 months after surgery. Results:  1196 participants were randomized (500 underwent cardiac, 346 thoracic and 350 abdominal surgery); 596 were allocated to placebo and 600 were allocated to gabapentin. Median length of hospital stay was similar in the two groups (gabapentin 5.94 (IQR 4.08-8.04) days, placebo 6.15 (IQR 4.22 – 8.97) days; hazard ratio 1.07, 95%CI 0.95-1.20, p=0.26). Overall, 384 participants experienced one or more serious adverse events (gabapentin 189/596, 31.7%; placebo 195/599, 32.6%), with some variation across surgical specialties. Conclusions:  Among patients undergoing major cardiac, thoracic and abdominal surgery, adding gabapentin to multimodal analgesic regimes did not alter the length of hospital stay, or the number of serious adverse events

A systems perspective on the death of a car company

Purpose – The aim of this paper is to understand how large and apparently successful organizations enter spirals of decline that are very difficult to reverse. The paper examines the case of Rover, once one of the largest car producers in the world, which collapsed in 2005. An analysis of strategic and operational choices made over a period of 40 years investigates the reasons for, and consequences of, a growing mismatch between the context faced by the company (industry dynamics, market conditions) and its operational capabilities, a mismatch that ultimately brought about the company's demise. Design/methodology/approach – The paper is based on interviews with 32 people, including senior managers (including four chief executives), government ministers and union officials who were key decision makers within, or close to, the company during the period 1968 and 2005. Secondary sources and documentary evidence (e.g. production and sales data) are used to build up a historical picture of the company and to depict its deteriorating financial and market position from 1968 onwards. Findings – The company was formed from a multitude of previously independent firms as part of a government‐sponsored agenda to build a UK National Champion in the car industry. The merged company failed due to several factors including poor product development processes, poor manufacturing performance, difficult labour relations, a very wide product portfolio and a lack of financial control. Although strenuous efforts were made to address those issues, including periods of whole or part ownership by British Aerospace, Honda and BMW, the company's position deteriorated until eventually production volumes were too low for viable operation. Practical implications – The case of Rover highlights the importance of what has been termed “the management unit” in complex systems. The management unit comprises processes and routines to deal with challenges such as managing product portfolios, connecting strategic and operational choices, and scanning and responding to the environment. In the case of Rover, a number of factors taken together generated excessive load on a management unit frequently operating under conditions of resource scarcity. We conclude that viewing corporate failure from a systems perspective, rather than in terms of shortcomings in specific subsystems, such as manufacturing or product development, yields insights often absent in the operations management literature. Originality/value – The paper is of value by showing corporate failure from a systems perspective, rather than in terms of shortcomings in specific subsystems, such as manufacturing or product development; and yields insights often absent in the operations management literature. The Rover case featured in the paper demonstrates the usefulness of systems ideas to understanding at least some types of failure, not as an alterative to capability‐based approaches, but in addition to them

Home-based narrowband UVB, topical corticosteroid or combination for children and adults with vitiligo: HI-Light Vitiligo three-arm RCT

BACKGROUND: Systematic reviews suggest that narrowband ultraviolet B light combined with treatments such as topical corticosteroids may be more effective than monotherapy for vitiligo. OBJECTIVE: To explore the clinical effectiveness and cost-effectiveness of topical corticosteroid monotherapy compared with (1) hand-held narrowband ultraviolet B light monotherapy and (2) hand-held narrowband ultraviolet B light/topical corticosteroid combination treatment for localised vitiligo. DESIGN: Pragmatic, three-arm, randomised controlled trial with 9 months of treatment and a 12-month follow-up. SETTING: Sixteen UK hospitals - participants were recruited from primary and secondary care and the community. PARTICIPANTS: Adults and children (aged ≥ 5 years) with active non-segmental vitiligo affecting ≤ 10% of their body area. INTERVENTIONS: Topical corticosteroids [mometasone furoate 0.1% (Elocon®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) plus dummy narrowband ultraviolet B light]; narrowband ultraviolet B light (narrowband ultraviolet B light plus placebo topical corticosteroids); or combination (topical corticosteroids plus narrowband ultraviolet B light). Topical corticosteroids were applied once daily on alternate weeks and narrowband ultraviolet B light was administered every other day in escalating doses, with a dose adjustment for erythema. All treatments were home based. MAIN OUTCOME MEASURES: The primary outcome was self-assessed treatment success for a chosen target patch after 9 months of treatment ('a lot less noticeable' or 'no longer noticeable' on the Vitiligo Noticeability Scale). Secondary outcomes included blinded assessment of primary outcome and percentage repigmentation, onset and maintenance of treatment response, quality of life, side effects, treatment burden and cost-effectiveness (cost per additional successful treatment). RESULTS: In total, 517 participants were randomised (adults, n = 398; and children, n =  119; 52% male; 57% paler skin types I-III, 43% darker skin types IV-VI). At the end of 9 months of treatment, 370 (72%) participants provided primary outcome data. The median percentage of narrowband ultraviolet B light treatment-days (actual/allocated) was 81% for topical corticosteroids, 77% for narrowband ultraviolet B light and 74% for combination groups; and for ointment was 79% for topical corticosteroids, 83% for narrowband ultraviolet B light and 77% for combination. Target patch location was head and neck (31%), hands and feet (32%), and rest of the body (37%). Target patch treatment 'success' was 20 out of 119 (17%) for topical corticosteroids, 27 out of 123 (22%) for narrowband ultraviolet B light and 34 out of 128 (27%) for combination. Combination treatment was superior to topical corticosteroids (adjusted risk difference 10.9%, 95% confidence interval 1.0% to 20.9%; p = 0.032; number needed to treat = 10). Narrowband ultraviolet B light was not superior to topical corticosteroids (adjusted risk difference 5.2%, 95% confidence interval -4.4% to 14.9%; p = 0.290; number needed to treat = 19). The secondary outcomes supported the primary analysis. Quality of life did not differ between the groups. Participants who adhered to the interventions for > 75% of the expected treatment protocol were more likely to achieve treatment success. Over 40% of participants had lost treatment response after 1 year with no treatment. Grade 3 or 4 erythema was experienced by 62 participants (12%) (three of whom were using the dummy) and transient skin thinning by 13 participants (2.5%) (two of whom were using the placebo). We observed no serious adverse treatment effects. For combination treatment compared with topical corticosteroids, the unadjusted incremental cost-effectiveness ratio was £2328.56 (adjusted £1932) per additional successful treatment (from an NHS perspective). LIMITATIONS: Relatively high loss to follow-up limits the interpretation of the trial findings, especially during the post-intervention follow-up phase. CONCLUSION: Hand-held narrowband ultraviolet B light plus topical corticosteroid combination treatment is superior to topical corticosteroids alone for treatment of localised vitiligo. Combination treatment was relatively safe and well tolerated, but was effective in around one-quarter of participants only. Whether or not combination treatment is cost-effective depends on how much decision-makers are willing to pay for the benefits observed. FUTURE WORK: Development and testing of new vitiligo treatments with a greater treatment response and longer-lasting effects are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17160087. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 64. See the NIHR Journals Library website for further project information

Countryside and Community Research Institute Podcast: Pride of Place(ment)

In this episode, we hear from this year's placement students Marie Steytler and Harry Batchelor. Marie and Harry joined us in September 2023 and have since immersed themselves within the collaborative and inclusive CCRI community. Join them as they discuss their placement experience so far with Nick Lewis, Research Assistant and Placement Coordinator, and learn more about the tasks they've been working on to support various CCRI research projects

The influence of HLA-linked genes on the severity of anti-GBM antibody-mediated nephritis

The influence of HLA-linked genes on anti-GBM antibody-mediated nephritis. Thirty-nine Caucasian patients with glomerulonephritis caused by autoantibodies to glomerular basement membrane (GBM) were studied. They were segregated into three groups depending on presentation: Group 1 (19 patients) were anuric or oliguric, group 2 (13 patients) had rapidly deteriorating renal function but were not oliguric, and group 3 (seven patients) had stable renal function. The incidence of HLA-DR2 was greatly increased; it was present in 34 of 38 patients in whom DR antigens were identified compared to 43 of 154 controls (Pc = 0.63 × 10-8, relative risk 36, etiological fraction 0.86). The incidence of HLA-B7 was also increased; present in 23 of 39 patients and 43 of 193 controls (Pc = 0.26 × 10-4, relative risk 5.0, etiological fraction 0.43). These data were analyzed for a third order association between HLA-DR2, HLA-B7, and anti-GBM disease. Such an association was probable for patients in group 1 (P = 0.27 × 10-6), likely for those in group 2 (P = 0.024) but unlikely for patients in group 3 (P = 0.62) suggesting HLA-B7-associated genes influence severity. Clinical results from a subset of the patients referred directly on presentation showed that patients who inherited HLA-B7 together with DR2 had significantly higher plasma creatinines, a greater proportion of glomeruli surrounded by crescents and a worse prognosis. Despite this there was little difference in severity of their lung disease.Influence des gènes liés à HLA sur la sévérité de la néphrite médiée par un anticorps anti-GMB. Trente-neuf malades blancs atteints de glomérulonéphrite due à des anticorps dirigés contre la membrane basale glomérulaire (GBM) ont été étudiés. Ils ont été divisés en trois groupes en fonction du tableau: ceux du groupe 1 (19 malades) étaient anuriques ou oliguriques, ceux du groupe 2 (13 malades) avaient une fonction rénale se détériorant rapidement mais n'étaient pas oliguriques, et ceux du groupe 3 (sept malades) avaient une fonction rénale stable. L'incidence de HLA-DR2 était très augmentée; il était présent chez 34 des 38 malades chez qui les antigènes DR avaient été identifiés, par rapport à 43 de 154 contrôles (Pc = 0,63 × 10-8, risque relatif 36, fraction étiologique 0,86). L'incidence de HLA-B7 était également augmentée; il était présent chez 23 des 39 malades et 43 de 193 contrôles (Pc = 0,26 × 10-4, risque relatif 5,0, fraction étiologique 0,43). Ces données ont été analysées pour une association du troisième ordre entre HLA-DR2, HLA-B7, et la maladie anti-GBM. Une telle association était probable pour les malades du groupe 1 (P = 0,27 × 10-6), possible pour ceux du groupe 2 (P = 0,024), mais improbable pour ceux du groupe 3 (P = 0,62), suggérant que les gènes associés à HLA-B7 influencent la sévérité. Les résultats cliniques d'un sous-groupe de malades adressés directement au début ont montré que ceux qui avaient hérité de HLA-B7 et de DR2 avaient des créatininémies significativement plus élvées, une plus grande proportion de glomérules entourés de croissants et un pronostic plus mauvais. Malgré cela, il y avait peu de différence de sévérité de leur maladie pulmonaire