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Hsin-Yi Tseng Jan Dreyer Abdullah Al Emran Dilini Gunatilake Mehdi Pirozyan Carleen Cullinane Ken Dutton-Regester Helen Rizos Nicholas K. Hayward Grant McArthur Peter Hersey Jessamy Tiffen Stuart Gallagher 《International journal of cancer. Journal international du cancer》2020,147(8):2176-2189
The treatment of melanoma has been markedly improved by the introduction of targeted therapies and checkpoint blockade immunotherapy. Unfortunately, resistance to these therapies remains a limitation. Novel anticancer therapeutics targeting the MCL1 anti-apoptotic protein have shown impressive responses in haematological cancers but are yet to be evaluated in melanoma. To assess the sensitivity of melanoma to new MCL1 inhibitors, we measured the response of 51 melanoma cell lines to the novel MCL1 inhibitor, S63845. Additionally, we assessed combination of this drug with inhibitors of the bromodomain and extra-terminal (BET) protein family of epigenetic readers, which we postulated would assist MCL1 inhibition by downregulating anti-apoptotic targets regulated by NF-kB such as BCLXL, BCL2A1 and XIAP, and by upregulating pro-apoptotic proteins including BIM and NOXA. Only 14% of melanoma cell lines showed sensitivity to S63845, however, combination of S63845 and I-BET151 induced highly synergistic apoptotic cell death in all melanoma lines tested and in an in vivo xenograft model. Cell death was dependent on caspases and BAX/BAK. Although the combination of drugs increased the BH3-only protein, BIM, and downregulated anti-apoptotic proteins such as BCL2A1, the importance of these proteins in inducing cell death varied between cell lines. ABT-199 or ABT-263 inhibitors against BCL2 or BCL2 and BCLXL, respectively, induced further cell death when combined with S63845 and I-BET151. The combination of MCL1 and BET inhibition appears to be a promising therapeutic approach for metastatic melanoma, and presents opportunities to add further BCL2 family inhibitors to overcome treatment resistance. 相似文献
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Suzanne Maman Lusajo Kajula Peter Balvanz Mrema Kilonzo Marta Mulawa Thespina Yamanis 《Global public health》2016,11(10):1202-1215
Gender inequality is at the core of the HIV patterns that are evident in sub-Saharan Africa. Gender-based violence (GBV) and lack of economic opportunity are important structural determinants of HIV risk. We piloted a microfinance and health promotion intervention among social networks of primarily young men in Dar es Salaam. Twenty-two individuals participated in the microfinance component and 30 peer leaders were recruited and trained in the peer health leadership component. We collected and analysed observational data from trainings, monitoring data on loan repayment, and reports of peer conversations to assess the feasibility and acceptability of the intervention. Eighteen of the loan recipients (82%) paid back their loans, and of these 15 (83%) received a second, larger loan. Among the loan defaulters, one died, one had chronic health problems, and two disappeared, one of whom was imprisoned for theft. The majority of conversations reported by peer health leaders focused on condoms, sexual partner selection, and HIV testing. Few peer leaders reported conversations about GBV. We demonstrated the feasibility and acceptability of this innovative HIV and GBV prevention intervention. The lessons learned from this pilot have informed the implementation of a cluster-randomised trial of the microfinance and peer health leadership intervention. 相似文献
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Peter Marhofer Malachy Columb Phil M. Hopkins Manfred Greher Daniela Marhofer Max R. Levi Bienzle Markus Zeitlinger 《British journal of anaesthesia》2019,122(4):525-531
Background
The efficacy of dexamethasone in extending the duration of local anaesthetic block is uncertain. In a randomised controlled triple blind crossover study in volunteers, we tested the hypothesis that neither i.v. nor perineurally administered dexamethasone prolongs the sensory block achieved with ropivacaine.Methods
Ultrasound-guided ulnar nerve blocks (ropivacaine 0.75% wt/vol, 3 ml, with saline 1 ml with or without dexamethasone 4 mg) were performed on three occasions in 24 male volunteers along with an i.v. injection of saline 1 ml with or without dexamethasone 4 mg. The combinations of saline and dexamethasone were as follows: control group, perineural and i.v. saline; perineural group, perineural dexamethasone and i.v. saline; i.v. group, perineural saline and i.v. dexamethasone. Sensory block was measured using a VAS in response to pinprick testing. The duration of sensory block was the primary outcome and time to onset of sensory block the secondary outcome.Results
All 24 subjects completed the trial. The median [inter-quartile range (IQR)] duration of sensory block was 6.87 (5.85–7.62) h in the control group, 7.37 (5.78–7.93) h in the perineural group and 7.37 (6.10–7.97) h in the i.v. group (P=0.61). There was also no significant difference in block onset time between the three groups.Conclusion
Dexamethasone 4 mg has no clinically relevant effect on the duration of sensory block provided by ropivacaine applied to the ulnar nerve.Clinical trial registration
DRKS, 00014604; EudraCT, 2018-001221-98. 相似文献67.
Peter D. Baade David C. Whiteman Monika Janda Anne E. Cust Rachel E. Neale Bernard Mark Smithers Adele C. Green Kiarash Khosrotehrani Victoria Mar H. Peter Soyer Joanne F. Aitken 《International journal of cancer. Journal international du cancer》2020,147(5):1391-1396
There is little long-term follow-up information about how the number of melanoma deaths and case fatality vary over time according to the measured thickness of melanoma at diagnosis. This population-based longitudinal cohort study examines patterns and trends in case fatality among 44,531 people in Queensland (Australia) diagnosed with a single invasive melanoma (International Classification of Diseases for Oncology, third revision [ICD-O-3], C44, Morphology 872–879) between 1987 and 2011, including 11,883 diagnosed between 1987 and 1996, with up to 20 years follow-up (to December 2016). The 20-year case fatality increased by thickness, with the percentage of melanoma deaths within 20 years of diagnosis being up to 4.8% for melanomas with measured thickness <0.80 mm, 10.6% for tumors 0.8 to <1.0 mm and generally more than 30% for melanomas measuring 3 mm and more. For melanomas <1.0 mm, most deaths occurred between 5 and 20 years after diagnosis, whereas for thicker melanomas the reverse was true with most deaths occurring within the first 5 years. Five-year case fatality decreased over successive calendar time periods for melanomas <1.0 mm, but not for melanomas ≥1.0 mm. These findings demonstrate that the time course for fatal melanomas varies markedly according to tumor thickness at diagnosis. Improved understanding of the patient factors and characteristics of melanomas, in addition to tumor thickness, which increase the likelihood of progression, is needed to guide clinical diagnosis, communication with patients and ongoing surveillance pathways of patients with potentially fatal lesions. 相似文献
68.
Marie Warrer Petersen Tine Sylvest Meyhoff Marie Helleberg Maj-Brit Nørregaard Kjær Anders Granholm Carl Johan Steensen Hjortsø Thomas Steen Jensen Morten Hylander Møller Peter Buhl Hjortrup Mik Wetterslev Gitte Kingo Vesterlund Lene Russell Vibeke Lind Jørgensen Klaus Tjelle Thomas Benfield Charlotte Suppli Ulrik Anne Sofie Andreasen Thomas Mohr Morten H. Bestle Lone Musaeus Poulsen Mette Friberg Hitz Thomas Hildebrandt Lene Surland Knudsen Anders Møller Christoffer Grant Sølling Anne Craveiro Brøchner Bodil Steen Rasmussen Henrik Nielsen Steffen Christensen Thomas Strøm Maria Cronhjort Rebecka Rubenson Wahlin Stephan Jakob Luca Cioccari Balasubramanian Venkatesh Naomi Hammond Vivekanand Jha Sheila Nainan Myatra Christian Gluud Theis Lange Anders Perner 《Acta anaesthesiologica Scandinavica》2020,64(9):1365-1375
Introduction
Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.Methods
The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.Discussion
The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.69.
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