Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

Sociodemographic and treatment-related correlates of fatigue in breast cancer survivors at an oncology clinic in Nigeria.

Background: Breast cancer survivors (BCS) still experience fatigue that may impair their quality of life even after completion of treatment. There is a need to understand the sociodemographic and treatment-related factors associated with this to develop relevant and effective interventions. Aim: To assess the relationship between cancer-related fatigue and sociodemographic and treatment-related factors in BCS. Materials and methods: This is a cross-sectional study involving 80 BCS attending the radiation oncology University College Hospital Ibadan. Their sociodemographic, disease and treatment characteristics were obtained. Fatigue Symptom Inventory was used to assess fatigue. A score of at least 3 on average fatigue severity item was taken as cut-off for clinically meaningful fatigue. Result: The mean age of patients was 51.5 years. The prevalence of fatigue was 22.5%. On univariate analysis, fatigue was significantly associated with younger age (p = 0.022), employment (p = 0.006), stage of the disease(p = 0.014), anthracycline-based chemotherapy (p = 0.026), last chemotherapy less than 1 year (p = 0.001). Using logistic regression analysis, stage (Odds ratio (OR) 5.115, 95% CI 1.029-25.438, p = 0.046), employment status (OR 52.224, 95% CI 3.611-755.899, p = 0.004) and year of last cycle chemotherapy (OR 6.375, 95% CI 1.108-36.680, p = 0.038) were associated with fatigue in BCS. Conclusion: About a quarter of BCS reported fatigue. Advance stage disease, employment status and receiving last course of chemotherapy less than a year are correlates of fatigue.

A systematic review of endometrial cancer clinical research in Africa.

BACKGROUND: Women in Africa are experiencing a rising burden of endometrial cancer. Research and investment to improve treatment and outcomes are critically needed. We systematically reviewed and characterized endometrial cancer-related research within a clinically relevant context to help organize and assess existing endometrial cancer research in Africa. METHODS: According to PRISMA guidelines, we searched online databases for published endometrial cancer articles from African countries from January 1, 2011, to July 20, 2021. Based on our inclusion and exclusion criteria, independent reviewers documented the study design, country/region, human development index, focus of research, type of interventions performed, and histologic and molecular type to illustrate the breadth of research coverage in each region. RESULTS: A total of 18 research articles were included. With an average Human Development Index (HDI) in Africa of 0.536, the average HDI of the represented countries in this study was 0.709. The majority (88.9%) of prospective endometrial cancer research articles in Africa were from North Africa, with Egypt encompassing 83.3% of the papers. Most of these studies focused on endometrial cancer diagnosis. Research on the treatment of endometrial cancer is still emerging (33% of papers). Of all included articles, only 11.1% represented Sub-Saharan Africa, where the majority population of black Africans reside. CONCLUSIONS: Endometrial cancer research in Africa is extremely limited, with the majority being concentrated in African countries with higher HDIs. As the incidence of endometrial cancer rises in Sub-Saharan Africa, there is a pressing need for more prospective clinical research to tackle the growing disease burden and improve outcomes.

Benign breast disease and breast cancer risk in African women: a case-control study.

PURPOSE: To examine the association between benign breast disease (BBD) and breast cancer (BC) in a heterogeneous population of African women. METHODS: BC cases and controls were enrolled in three sub-Saharan African countries, Nigeria, Cameroon, and Uganda, between 1998 and 2018. Multivariable logistic regression was used to test the association between BBD and BC. Risk factors dually associated with BBD and BC were selected. Using a parametric mediation analysis model, we assessed if selected BC risk factors were mediated by BBD. RESULTS: Of 6,274 participants, 55.6% (3,478) were breast cancer cases. 360 (5.7%) self-reported BBD. Fibroadenoma (46.8%) was the most commonly reported BBD. Women with a self-reported history of BBD had greater odds of developing BC than those without (adjusted odds ratio [aOR] 1.47, 95% CI 1.13-1.91). Biopsy-confirmed BBD was associated with BC (aOR 2.25, 95% CI 1.26-4.02). BBD did not significantly mediate the effects of any of the selected BC risk factors. CONCLUSIONS: In this study, BBD was associated with BC and did not significantly mediate the effects of selected BC risk factors.

Mapping of Radiation Oncology and Gynecologic Oncology Services Available to Treat the Growing Burden of Cervical Cancer in Africa.

PURPOSE: To meet the demand for cervical cancer care in Africa, access to surgical and radiation therapy services needs to be understood. We thus mapped the availability of gynecologic and radiation therapy equipment and staffing for treating cervical cancer. METHODS AND MATERIALS: We collected data on gynecologic and radiation oncology staffing, equipment, and infrastructure capacities across Africa. Data was obtained from February to July 2021 through collaboration with international partners using Research Electronic Data Capture. Cancer incidence was taken from the International Agency for Research on Cancer's GLOBOCAN 2020 database. Treatment capacity, including the numbers of radiation oncologists, radiation therapists, physicists, gynecologic oncologists, and hospitals performing gynecologic surgeries, was calculated per 1000 cervical cancer cases. Adequate capacity was defined as 2 radiation oncologists and 2 gynecologic oncologists per 1000 cervical cancer cases. RESULTS: Forty-three of 54 African countries (79.6%) responded, and data were not reported for 11 countries (20.4%). Respondents from 31 countries (57.4%) reported access to specialist gynecologic oncology services, but staffing was adequate in only 11 countries (20.4%). Six countries (11%) reported that generalist obstetrician-gynecologists perform radical hysterectomies. Radiation oncologist access was available in 39 countries (72.2%), but staffing was adequate in only 16 countries (29.6%). Six countries (11%) had adequate staffing for both gynecologic and radiation oncology; 7 countries (13%) had no radiation or gynecologic oncologists. Access to external beam radiation therapy was available in 31 countries (57.4%), and access to brachytherapy was available in 25 countries (46.3%). The number of countries with training programs in gynecologic oncology, radiation oncology, medical physics, and radiation therapy were 14 (26%), 16 (30%), 11 (20%), and 17 (31%), respectively. CONCLUSIONS: We identified areas needing comprehensive cervical cancer care infrastructure, human resources, and training programs. There are major gaps in access to radiation oncologists and trained gynecologic oncologists in Africa.

Tumor sequencing of African ancestry reveals differences in clinically relevant alterations across common cancers.

Cancer genomes from patients with African (AFR) ancestry have been poorly studied in clinical research. We leverage two large genomic cohorts to investigate the relationship between genomic alterations and AFR ancestry in six common cancers. Cross-cancer type associations, such as an enrichment of MYC amplification with AFR ancestry in lung, breast, and prostate cancers, and depletion of BRAF alterations are observed in colorectal and pancreatic cancers. There are differences in actionable alterations, such as depletion of KRAS G12C and EGFR L858R, and enrichment of ROS1 fusion with AFR ancestry in lung cancers. Interestingly, in lung cancer, KRAS mutations are less common in both smokers and non-smokers with AFR ancestry, whereas the association of TP53 mutations with AFR ancestry is only seen in smokers, suggesting an ancestry-environment interaction that modifies driver rates. Our study highlights the need to increase representation of patients with AFR ancestry in drug development and biomarker discovery.

Benign breast disease and breast cancer risk in African women: A case-control study.

Purpose: To examine the association between benign breast disease (BBD) and breast cancer (BC) in a heterogeneous population of African women. Methods: BC cases and matched controls were enrolled in three sub-Saharan African countries, Nigeria Cameroon, and Uganda, between 1998-2018. Multivariable logistic regression was used to test the association between BBD and BC. Risk factors dually associated with BBD and BC were selected. Using a parametric mediation analysis model, we assessed if selected BC risk factors were mediated by BBD. Results: Of 6418 participants, 55.7% (3572) were breast cancer cases. 360 (5.7%) self-reported BBD. Fibroadenoma (46.8%) was the most reported BBD. Women with a self-reported history of BBD had greater odds of developing BC than those without (adjusted odds ratio [aOR] = 1.47, 95% CI: 1.13-1.91). Biopsy-confirmed BBD was associated with BC (aOR = 3.11, 95% CI: 1.78-5.44). BBD did not significantly mediate the effects of any of the selected BC risk factors. Conclusions: In this study, BBD was associated with BC and did not significantly mediate the effects of selected BC risk factors.

The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer.

Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regulated gene expression. For this reason, there is great interested in the development of new therapies targeting KDM1A and KDM5B, particularly in the context of castrate resistant PCa (CRPC), where conventional androgen deprivation therapies and androgen receptor signalling inhibitors are no longer effective. As there is no curative therapy for CRPC, new approaches are urgently required to suppress androgen signalling that prevent, delay or reverse progression to the castrate resistant state. While the contribution of KDM1A to PCa is well established, the exact contribution of KDM5B to PCa is less well understood. However, there is evidence that KDM5B is implicated in numerous pro-oncogenic mechanisms in many different types of cancer, including the hypoxic response, immune evasion and PI3/AKT signalling. Here we elucidate the individual and cooperative functions of KDM1A and KDM5B in PCa. We show that KDM5B mRNA and protein expression is elevated in localised and advanced PCa. We show that the KDM5 inhibitor, CPI-455, impairs androgen regulated transcription and alternative splicing. Consistent with the established role of KDM1A and KDM5B as AR coregulators, we found that individual pharmacologic inhibition of KDM1A and KDM5 by namoline and CPI-455 respectively, impairs androgen regulated transcription. Notably, combined inhibition of KDM1A and KDM5 downregulates AR expression in CRPC cells. Furthermore, combined KDM1A and KDM5 inhibition impairs PCa cell proliferation and invasion more than individual inhibition of KDM1A and KDM5B. Collectively our study has identified individual and cooperative mechanisms involving KDM1A and KDM5 in androgen signalling in PCa. Our findings support the further development of KDM1A and KDM5B inhibitors to treat advanced PCa. Further work is now required to confirm the therapeutic feasibility of combined inhibition of KDM1A and KDM5B as a novel therapeutic strategy for targeting AR positive CRPC.

The Prevalence of Prostate Cancer Among Young Men Below 55 Years of Age in Nigeria.

INTRODUCTION: Prostate cancer is the most common cancer in men. It was initially a disease of older men above the age of 55 years. Of recent, there has been reports of increase in the number of young men <55 years with prostate cancer (PCa). The disease in this age group has been reported to be more lethal because of aggressive characteristics and metastatic potential. Different populations have different proportions of young-onset PCa. The aim of this study was to determine the proportion of young men aged <55 years with PCa in Nigeria. METHODS: Data on the prevalence of young men <55 years with PCa was extracted from the 2022 report of the prevalence of cancer in Nigeria from 2009 to 2016 based on the records of 15 major Cancer Registries in Nigeria. This was a publication of the Nigerian Ministry of Health and represents the most up to date data. RESULTS: In 4864 men diagnosed with malignancies before age 55, PCa was the second common, following liver cancer. Out of a total of 4091 cases of PCa in all age groups, 355 were diagnosed in men <55 years representing 8.86%. Furthermore, the proportion of young men with the disease in the Northern part of the country was 11.72%, whereas in the South, it was 7.77%. CONCLUSIONS: PCa is the second most common cancer in young Nigerian men aged< 55 years preceded by liver cancer. The proportion of young men with PCa was 8.86%. It is therefore important to consider PCa in young men as a different entity and develop appropriate ways to control this disease to ensure survival and good quality of life.

EGFR and HER2 expression in cervical cancer patients in Ibadan, Nigeria.

Cervical cancer is a leading cause of cancer-related deaths in developing countries, including Nigeria where it is the second most common female malignancy. Studies from elsewhere have demonstrated the relationship between epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) and advanced cervical cancer. However, we are not aware of such studies in Nigerian patients. The main objective of the study was to determine the prevalence of EGFR or HER1 and HER2 protein expression in cervical cancers and to determine their impact on overall survival. Clinical data and formalin-embedded tissue blocks of 124 patients who presented in the Radiation Oncology Department, University College Hospital (UCH), from 2006 to 2015 and had their histological diagnosis at the Pathology Department, UCH were retrieved and analysed for EGFR and HER2 expression using immunohistochemistry. EGFR expression was analysed using the immunoreactivity score by Remmele and Stegner. HER2 was analysed using the Hercep® test kit guidelines. Survival analysis was done using Kaplan-Meier and Cox regression analysis. Missing data were reported as missing, not documented. EGFR (immunoreactivity score > 4) was overexpressed in 26.6% of the 124 cervical tissue samples tested. Most patients whose samples were positive for EGFR were young, had squamous cell carcinoma and advanced diseases. HER2 was overexpressed in two samples (1.6%). The 5-year overall survival rate of the patients was 28.3%. The 5-year survival rate of patients who were EGFR positive was 9.5% and 34.1% for those who were EGFR negative. Screening for EGFR should be considered in cervical cancer patients. HER2 was overexpressed in two cervical tissue samples in this study and may be of poor interest as a potential target in the management of cervical cancer patients. Large prospective multi-institutional studies should be considered to further explore the relationship between EGFR and survival in cervical cancer patients.

The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer.

Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing androgen biosynthesis or via AR signalling inhibition (ARSi) are common treatments. The N6-methyladenosine (m6A) RNA modification is involved in regulating mRNA expression, translation, and alternative splicing, and through these mechanisms has been implicated in cancer development and progression. RNA-m6A is dynamically regulated by the METTL3 RNA methyltransferase complex and the FTO and ALKBH5 demethylases. While there is evidence supporting a role for aberrant METTL3 in many cancer types, including localised PCa, the wider contribution of METTL3, and by inference m6A, in androgen signalling in PCa remains poorly understood. Therefore, the aim of this study was to investigate the expression of METTL3 in PCa patients and study the clinical and functional relevance of METTL3 in PCa. It was found that METTL3 is aberrantly expressed in PCa patient samples and that siRNA-mediated METTL3 knockdown or METTL3-pharmacological inhibition significantly alters the basal and androgen-regulated transcriptome in PCa, which supports targeting m6A as a novel approach to modulate androgen signalling in PCa.

Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer.

Androgen deprivation therapies (ADTs) are important treatments which inhibit androgen-induced prostate cancer (PCa) progression by either preventing androgen biosynthesis (e.g. abiraterone) or by antagonizing androgen receptor (AR) function (e.g. bicalutamide, enzalutamide, darolutamide). A major limitation of current ADTs is they often remain effective for limited durations after which patients commonly progress to a lethal and incurable form of PCa, called castration-resistant prostate cancer (CRPC) where the AR continues to orchestrate pro-oncogenic signalling. Indeed, the increasing numbers of ADT-related treatment-emergent neuroendocrine-like prostate cancers (NePC), which lack AR and are thus insensitive to ADT, represents a major therapeutic challenge. There is therefore an urgent need to better understand the mechanisms of AR action in hormone dependent disease and the progression to CRPC, to enable the development of new approaches to prevent, reverse or delay ADT-resistance. Interestingly the AR regulates distinct transcriptional networks in hormone dependent and CRPC, and this appears to be related to the aberrant function of key AR-epigenetic coregulator enzymes including the lysine demethylase 1 (LSD1/KDM1A). In this review we summarize the current best status of anti-androgen clinical trials, the potential for novel combination therapies and we explore recent advances in the development of novel epigenetic targeted therapies that may be relevant to prevent or reverse disease progression in patients with advanced CRPC.

Fatigue as a complicating factor in the recovery of breast cancer survivors treated at an oncology clinic in South West Nigeria: a case-control study.

Purpose: Recovering cancer survivors hope to return to their premorbid lifestyle after treatment and be free from the disease. They are, however, faced with some psychosocial issues, including fatigue, which could negatively impact their quality of life. With increasing cancer awareness and improvement in treatment, it is expected that the number of cancer survivors will increase in Nigeria. Little has, however, been done with regard to survivorship care in the country. It is important to explore fatigue in this group of patients with a view to find ways of reducing it to the barest minimum. Aim: To assess the level of fatigue in breast cancer survivors on follow-up visit at a radiation oncology clinic and compare it with age and sex-matched apparently healthy controls. Materials and Methods: Fatigue levels were obtained using the Fatigue Symptom Inventory (FSI). Kruskal-Wallis H test was used to compare the FSI scores in cases and controls. Chi-squared test was used for comparison of proportions. Level of significance was set at 5%. Results: Seventy cancer survivors (cases) and 70 apparently healthy age (±1)-matched controls were recruited. The prevalence of fatigue was higher among cases than controls (24.3% versus 10%; p = 0.025). Breast cancer survivors reported significantly worse fatigue on the day they were most fatigued (p = 0.017), least fatigued (0.047) and fatigued on average (p = 0.006) compared to controls. Fatigue also significantly interferes with the ability to concentrate (p = 0.040) and relate with people (p = 0.002) more in cases compared to controls. While fatigue was more common in the morning and afternoon in breast cancer survivors, fatigue either occurred more in the evening or followed no daily pattern in the controls. Conclusion: Breast cancer survivors reported worse fatigue, suggesting the need to include fatigue screening as part of post-treatment follow-up. There is also a need to investigate the factors responsible for this and explore ways of reducing or eliminating it.

Breast Cancer in Adolescents and Young Adults Less Than 40 Years of Age in Nigeria: A Retrospective Analysis.

Background: Breast cancer among adolescents and young adult (AYA) females aged 15-39 years is associated with different patterns of aggressiveness, as well as psychosocial and economic issues. At present, the burden of breast cancer among this age group is unknown in Nigeria. There is a need to determine the proportion of AYA with breast cancer in Nigeria. This will inform the development of breast cancer care programs appropriate for this age group. Objective: The objective of this study was to highlight the burden of breast cancer with an emphasis on AYAs in Nigeria and its implications. Methods: A retrospective review of data from cancer registries in Nigeria between 2009 and 2016 was carried out. Result: s. Among AYA females in Nigeria, breast cancer was by far the most common cancer, constituting 50% of all cancers and 51% (2798 of 5469) of all breast cancer cases. IA third (30.8%) of breast cancer cases in all centers studied were AYAs. Conclusion: The high proportion of AYA with breast cancer is an important feature suggesting that urgent actions are required to ensure early detection and improve breast cancer care among this age group.

Innovative Strategies for Developing Biomarker-Informed Cancer Clinical Trials to Accelerate Progress in Precision Oncology in Sub-Saharan Africa.

Well-designed, pragmatic, patient-centered clinical trials in low- and middle-income countries are essential to drive approval of more effective and less toxic cancer medicines to address the rising burden of cancer among populations in low- and middle-income countries. Moreover, through reverse innovation, clinical trials informed by genomic research enable development of precision medicine strategies for underserved populations within all populations. The African continent is home to many low- and middle-income countries; yet, it has seen very few cancer clinical trials. Considering that Africa is the cradle of humanity, with its diverse populations and geography, this represents a missed opportunity to understand the heterogeneity of cancer genomes and their implications for developmental therapeutics. Since 1998, the Nigerian Breast Cancer Study Group has striven to gain a better understanding of the root causes of breast cancer and accelerate progress in clinical research that will benefit the African ancestry diaspora globally through deployment of innovative "leapfrog" technologies. The University of Chicago supports interdisciplinary and interprofessional teams of researchers through the African Cancer Leaders Institute and in partnership with the African Organization for Research and Training in Cancer. By fostering public-private partnerships, the African Organization for Research and Training in Cancer can identify and integrate significant resources needed to build regional networks and establish clinical trial coordinating centers across African countries, enabling resources to be developed and shared equitably. Such resources include a standardized curriculum for specialist training in oncology, including medical oncology and oncology nursing, to increase the numbers of qualified team leaders and principal investigators. Adequate support for study participants-financial and psychosocial-and patient navigation services will be important in growing a clinical trials network. Finally, full participation of African clinical researchers in global oncology trials will ensure workforce retention in Africa and improve financial security and job satisfaction of health professionals on the African continent.

Oncology Training Needs Assessment Among Health Care Professionals in Nigeria.

PURPOSE: This study investigated the status of training and preparedness for oncology practice and research and degree of interprofessional collaboration among health care professionals in the six geopolitical regions of Nigeria. METHODS: A convergent parallel mixed methods design was used. Three hundred seventeen respondents completed a three-part, online questionnaire. Self-rated competencies in oncology research (26 items), oncology practice (16 items), and interprofessional collaboration (nine items) were assessed with a one- to five-point Likert scale. Six key informant and 24 in-depth interviews were conducted. Descriptive statistics, analysis of variance, and pairwise t-test were used to analyze the quantitative data, whereas thematic analysis was used for the qualitative data. RESULTS: Respondents were mostly female (65.6%) with a mean age of 40.5 ± 8.3 years. Respondents include 178 nurses (56.2%), 93 medical doctors (29.3%), and 46 pharmacists (14.5%). Self-assessed competencies in oncology practice differed significantly across the three groups of health care professionals (F = 4.789, P = .009). However, there was no significant difference across professions for competency in oncology research (F = 1.256, P = .286) and interprofessional collaboration (F = 1.120, P = .327). The majority of respondents (267, 82.4%) felt that educational opportunities in oncology-associated research in the country are inadequate and that this has implications for practice. Key training gaps reported include poor preparedness in data analysis and bioinformatics (138, 43.5%), writing clinical trials (119, 37.5%), and writing grant/research proposals (105, 33.1%). Challenges contributing to gaps in cancer research include few trained oncology specialists, low funding for research, and inadequate interprofessional collaboration. CONCLUSION: This study highlights gaps in oncology training and practice and an urgent need for interventions to enhance interprofessional training to improve quality of cancer care in Nigeria. These would accelerate progress toward strengthening the health care system and reducing global disparities in cancer outcomes.

How COVID-19 changed clinical research strategies: a global survey.

OBJECTIVE: Clinical research has faced new challenges during the COVID-19 pandemic, leading to excessive operational demands affecting all stakeholders. We evaluated the impact of COVID-19 on clinical research strategies and compared different adaptations by regulatory bodies and academic research institutions in a global context, exploring what can be learned for possible future pandemics. METHODS: We conducted a cross-sectional online survey and identified and assessed different COVID-19-specific adaptation strategies used by academic research institutions and regulatory bodies. RESULTS: All 19 participating academic research institutions developed and followed similar strategies, including preventive measures, manpower recruitment, and prioritisation of COVID-19 projects. In contrast, measures for centralised management or coordination of COVID-19 projects, project preselection, and funding were handled differently amongst institutions. Regulatory bodies responded similarly to the pandemic by implementing fast-track authorisation procedures for COVID-19 projects and developing guidance documents. Quality and consistency of the information and advice provided was rated differently amongst institutions. CONCLUSION: Both academic research institutions and regulatory bodies worldwide were able to cope with challenges during the COVID-19 pandemic by developing similar strategies. We identified some unique approaches to ensure fast and efficient responses to a pandemic. Ethical concerns should be addressed in any new decision-making process.

Clinical and molecular significance of the RNA m6A methyltransferase complex in prostate cancer.

N6-methyladenosine (m6A) is the most abundant internal mRNA modification and is dynamically regulated through distinct protein complexes that methylate, demethylate, and/or interpret the m6A modification. These proteins, and the m6A modification, are involved in the regulation of gene expression, RNA stability, splicing and translation. Given its role in these crucial processes, m6A has been implicated in many diseases, including in cancer development and progression. Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in men and recent studies support a role for m6A in PCa. Despite this, the literature currently lacks an integrated analysis of the expression of key components of the m6A RNA methyltransferase complex, both in PCa patients and in well-established cell line models. For this reason, this study used immunohistochemistry and functional studies to investigate the mechanistic and clinical significance of the METTL3, METTL14, WTAP and CBLL1 components of the m6A methyltransferase complex in PCa specimens and cell lines. Expression of METTL3 and CBLL1, but not METTL14 and WTAP, was associated with poorer PCa patient outcomes. Expression of METTL3, METTL14, WTAP and CBLL1 was higher in PCa cells compared with non-malignant prostate cells, with the highest expression seen in castrate-sensitive, androgen-responsive PCa cells. Moreover, in PCa cell lines, expression of METTL3 and WTAP was found to be androgen-regulated. To investigate the mechanistic role(s) of the m6A methyltransferase complex in PCa cells, short hairpin RNA (shRNA)-mediated knockdown coupled with next generation sequencing was used to determine the transcriptome-wide roles of METTL3, the catalytic subunit of the m6A methyltransferase complex. Functional depletion of METTL3 resulted in upregulation of the androgen receptor (AR), together with 134 AR-regulated genes. METTL3 knockdown also resulted in altered splicing, and enrichment of cell cycle, DNA repair and metabolic pathways. Collectively, this study identified the functional and clinical significance of four essential m6A complex components in PCa patient specimens and cell lines for the first time. Further studies are now warranted to determine the potential therapeutic relevance of METTL3 inhibitors in development to treat leukaemia to benefit patients with PCa.

Emerging Use of Public-Private Partnerships in Public Radiotherapy Facilities in Nigeria.

PURPOSE: Radiotherapy (RT) treatment at public hospitals in Nigeria is often interrupted by prolonged periods of machine breakdown because of insufficient funds for maintenance and repair. These delays have prompted the uptake of public-private partnerships (PPPs) to acquire and maintain RT equipment. This study aimed to understand Nigeria's current RT capacity and the impact of PPPs on RT availability and cost. METHODS: Eleven radiation oncologists, each representing one of the 11 RT centers in Nigeria (eight public and three private), were invited to complete a survey on the type, status, acquisition, and maintenance plan of existing RT equipment, cost incurred by patients for external-beam radiation (EBRT) and brachytherapy treatment, and number of patients treated per year on each machine. Type and status of equipment at nonresponding facilities were obtained through literature review and confirmed with the facility. RESULTS: A total of eight (81%) respondents completed the survey, all representing public centers, three of which reported PPP use. They reported 11 megavoltage units in total (seven linear accelerators [LINACs] and four Cobalt-60s) and 10 brachytherapy afterloaders. Of those, 57% (4/7) of the LINACs, 100% (4/4) of the Cobalt-60s, and 63% (7/11) of the afterloaders were in clinical use. All commissioned equipment supported by PPPs (three LINACs and one afterloader) were in operation. The public EBRT equipment were nonfunctional 35% of the year (resulting in 60% fewer patients treated per year). The PPP EBRT and afterloaders did not experience any periods of breakdown, but PPP costs were 338% higher than public equipment. CONCLUSION: This study characterizes the use of PPP as a more reliable method of RT delivery in Nigeria, albeit at higher costs.