THE HOMEOBOX PROTEIN HOXC10 IS OVEREXPRESSED IN BREAST CANCER AND INCREASES RESISTANCE TO CHEMOTHERAPY

Background. Drug resistance is a major limiting factor in the success of targeted cancer therapies resulting in failure of treatment. A molecular understanding of the underlying mechanisms is essential to predict, prevent and overcome drug resistance. Though many pathways have been studied, key factors driving these pathways have not been largely identified. Methods. Using a tiling array of all four HOX clusters, we identified HOXC10 as being among the highly overexpressed genes in breast cancer. Then using a panel of cell lines that either stably overexpress exogenous HOXC10 or cell lines with stably downregulated endogenous HOXC10 (mediated by shRNA), we investigated the role of HOXC10 in proliferation, response to chemotherapy treatment and repair of DNA damage. Mechanistically, we studied the consequence of HOXC10 binding to CDK7 during response to chemotherapy. Finally, we investigated the importance of HOXC10 as a prognostic marker in breast cancer. Results. HOXC10 is frequently overexpressed both in primary breast tumors and distant metastatic tissues. HOXC10 promotes continuous growth by facilitating G1/S progression and replication resumption with higher E2F1 activity. Higher levels of HOXC10 expression is also associated with worse relapse-free survival, and overall survival in chemotherapy treated patients. In fact, HOXC10 is upregulated in chemoresistant MCF7 cell lines, and MDA-MB-231 and SUM-159 xenografts. When cells are exposed to DNA damaging agents, HOXC10 suppresses apoptosis, enhances DNA damage repair and NF-κβ activity, reducing susceptibility to drug treatment. Further investigation to HOXC10 binding partners after chemotherapy treatment led to the finding that HOXC10 binds to and stimulates the kinase activity of CDK7 towards its substrate, RNA polymerase II, and the association of CDK7 with XPD. This allows HOXC10 to supports the resumption of transcription and the recovery of cells after DNA damage. Consequently, inhibiting CDK7 pharmacologically or reducing its levels using siRNA reduced the protective effect of HOXC10 on drug treated cells. Conclusions. These data suggest that HOXC10 plays a key role during progression and recurrence of breast cancers through modulating different survival pathways. Therefore, decreasing the levels or function of HOXC10 in breast cancers might be a promising strategy to reduce chemotherapy resistance

Bridging the gap in African biodiversity genomics and bioinformatics:Open Institute of the African BioGenome Project:

The Open Institute of the African BioGenome Project empowers African scientists and institutions with the skill sets, capacity and infrastructure to advance scientific knowledge and innovation and drive economic growth

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries

BACKGROUND: The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe. METHODS: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries. RESULTS: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease. CONCLUSIONS: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

The combined analysis of solid and liquid biopsies provides additional clinical information to improve patient care

Aim: To investigate if the genetic information provided by sequencing of both solid and liquid biopsies can shed light on tumor heterogeneity, and to understand the clinical usefulness of adding blood profiling to standard tissue analysis in cancer care.Methods: Data from 351 patients with stage IV solid tumors for whom molecular profiling of their solid and liquid biopsies was available were studied, with a focus on the discrepant molecular information found between tissue and blood samples.Results: In 86% of patients, solid and liquid biopsies provided different molecular information. Discrepant gene mutations with a functional impact on the corresponding protein were studied in detail. In 97% of cases, these additional mutations provided clinical value, mainly predicting sensitivity or resistance to targeted therapies. Specifically, 42% of the mutations found only in the liquid biopsy were directly predictive of approved therapies (80% targeted therapies), while 54% were inclusion criteria for molecularly-matched trials.Conclusion: This study suggests that the addition of blood profiling should be considered in routine clinical oncology, especially for patients with metastatic disease where integrated analysis of solid and liquid biopsies provides a more complete characterization of tumor heterogeneity and provides valuable clinical information for patient treatment

Dimensions of expansion for configuring learning spaces in global work

Purpose: Technological innovation and the flexibilisation of labour markets have expanded the pool of workers engaged in globally distributed work. This paper aims to propose an analytical framework to understand and support the productive professional learning of those engaged in global work. Drawing on the theory of expansive learning in the cultural-historical activity theory tradition the study aims to stimulate and enrich the conceptual notion of work as a learning space in the discussion of workplace learning particularly in global work. Design/methodology/approach: Iteration between theory and data is applied to identify the dimensions of expansion for the configuration of learning spaces in global work. Data are drawn from the experiences of 10 professionals selected by purposive sampling in Austria, Italy, the Netherlands and Singapore. Findings: Six dimensions of expansion are identified as challenging and potentially empowering for professionals’ configuration of learning spaces in global work: social-spatial, material-instrumental, moral-ethical, political-economic, personal-professional and temporal-developmental. Originality/value: The conceptual framework for the dimensions of expansion of learning spaces provides the broad strokes for reflexive curricula that democratise the learning and development of professionals in global work, who are currently underserved given the national orientation of vocational education and training and professional development ecosystems.publishedVersionPeer reviewe

Development of a pediatric ophthalmology academic partnership between Canada and Ethiopia: a situational analysis

Abstract Background Educational capacity building in pediatric ophthalmology is necessary to address the burden of childhood blindness in Ethiopia. Residency and fellowship training at Addis Ababa University (AAU) have been enhanced with support from the University of Toronto (UofT), following the established Toronto Addis Ababa Academic Collaboration (TAAAC). Our aim was to assess the feasibility of implementing a pediatric ophthalmology fellowship at AAU with support from UofT, modeled by successful postgraduate medical education within TAAAC. Methods A situational analysis, including a needs assessment, was conducted at Menelik II Hospital, Addis Ababa. Staff expertise, equipment and infrastructure were compared to International Council of Ophthalmology fellowship guidelines. Patient volumes were assessed through medical chart review. Local training needs were evaluated. A strategic working meeting facilitated program specification. Results The faculty consisted of 11 ophthalmologists, including 2 pediatric specialists. Fourteen thousand six hundred twenty-seven medical and three thousand six hundred forty-one surgical pediatric cases were seen in the previous year. A 2-year fellowship incorporating anterior segment, retinoblastoma, strabismus, and retinopathy of prematurity modules was developed. Research collaborations, didactic teaching, and surgical supervision were identified as priorities requiring support. Quality standard indicators included faculty feedback, case log review and formal examination. Telemedicine, development of a larger eye hospital and partnerships to support equipment maintenance were identified as strategies to manage implementation barriers. Conclusions The situational analysis provided a way forward for the development of a pediatric ophthalmology fellowship, the first of its kind in Eastern Africa. Learning outcomes are feasible given high patient volumes, qualified staff supervision and sufficient equipment. Strategic partnerships may ensure resource sustainability