Cancer in sub-Saharan Africa: a Lancet Oncology Commission.

In sub-Saharan Africa (SSA), urgent action is needed to curb a growing crisis in cancer incidence and mortality. Without rapid interventions, data estimates show a major increase in cancer mortality from 520 348 in 2020 to about 1 million deaths per year by 2030. Here, we detail the state of cancer in SSA, recommend key actions on the basis of analysis, and highlight case studies and successful models that can be emulated, adapted, or improved across the region to reduce the growing cancer crises. Recommended actions begin with the need to develop or update national cancer control plans in each country. Plans must include childhood cancer plans, managing comorbidities such as HIV and malnutrition, a reliable and predictable supply of medication, and the provision of psychosocial, supportive, and palliative care. Plans should also engage traditional, complementary, and alternative medical practices employed by more than 80% of SSA populations and pathways to reduce missed diagnoses and late referrals. More substantial investment is needed in developing cancer registries and cancer diagnostics for core cancer tests. We show that investments in, and increased adoption of, some approaches used during the COVID-19 pandemic, such as hypofractionated radiotherapy and telehealth, can substantially increase access to cancer care in Africa, accelerate cancer prevention and control efforts, increase survival, and save billions of US dollars over the next decade. The involvement of African First Ladies in cancer prevention efforts represents one practical approach that should be amplified across SSA. Moreover, investments in workforce training are crucial to prevent millions of avoidable deaths by 2030. We present a framework that can be used to strategically plan cancer research enhancement in SSA, with investments in research that can produce a return on investment and help drive policy and effective collaborations. Expansion of universal health coverage to incorporate cancer into essential benefits packages is also vital. Implementation of the recommended actions in this Commission will be crucial for reducing the growing cancer crises in SSA and achieving political commitments to the UN Sustainable Development Goals to reduce premature mortality from non-communicable diseases by a third by 2030.

Mechanotransduction map: simulation model, molecular pathway, gene set.

MOTIVATION: Mechanotransduction--the ability to output a biochemical signal from a mechanical input--is related to the initiation and progression of a broad spectrum of molecular events. Yet, the characterization of mechanotransduction lacks some of the most basic tools as, for instance, it can hardly be recognized by enrichment analysis tools, nor could we find any pathway representation. This greatly limits computational testing and hypothesis generation on mechanotransduction biological relevance and involvement in disease or physiological mechanisms. RESULTS: We here present a molecular map of mechanotransduction, built in CellDesigner to warrant that maximum information is embedded in a compact network format. To validate the map's necessity we tested its redundancy in comparison with existing pathways, and to estimate its sufficiency, we quantified its ability to reproduce biological events with dynamic simulations, using Signaling Petri Networks. AVAILABILITY AND IMPLEMENTATION: SMBL language map is available in the Supplementary Data: core_map.xml, basic_map.xml. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SPNConverter: a new link between static and dynamic complex network analysis.

SUMMARY: The signaling Petri net (SPN) simulator, designed to provide insights into the trends of molecules' activity levels in response to an external stimulus, contributes to the systems biology necessity of analyzing the dynamics of large-scale cellular networks. Implemented into the freely available software, BioLayout Express(3D), the simulator is publicly available and easy to use, provided the input files are prepared in the GraphML format, typically using the network editing software, yEd, and standards specific to the software. However, analysis of complex networks represented using other systems biology formatting languages (on which popular software, such as CellDesigner and Cytoscape, are based) requires manual manipulation, a step that is prone to error and limits the use of the SPN simulator in BioLayout Express(3D). To overcome this, we present a Cytoscape plug-in that enables users to automatically convert networks for analysis with the SPN simulator from the standard systems biology markup language. The automation of this step opens the SPN simulator to a far larger user group than has previously been possible. AVAILABILITY AND IMPLEMENTATION: Distributed under the GNU General Public License Version 3 at http://apps.cytoscape.org/apps/spnconverter.

Unification of Efforts to Improve Global Access to Cancer Therapeutics: Report From the 2022/2023 Access to Essential Cancer Medicines Stakeholder Summit.

PURPOSE: There is an urgent need to improve access to cancer therapy globally. Several independent initiatives have been undertaken to improve access to cancer medicines, and additional new initiatives are in development. Improved sharing of experiences and increased collaboration are needed to achieve substantial improvements in global access to essential oncology medicines. METHODS: The inaugural Access to Essential Cancer Medicines Stakeholder Meeting was organized by ASCO and convened at the June 2022 ASCO Annual Meeting in Chicago, IL, with two subsequent meetings, Union for International Cancer Control World Cancer Congress held in Geneva, Switzerland, in October 2022 and at the ASCO Annual Meeting in June of 2023. Invited stakeholders included representatives from cancer institutes, physicians, researchers, professional societies, the pharmaceutical industry, patient advocacy organizations, funders, cancer organizations and foundations, policy makers, and regulatory bodies. The session was moderated by ASCO. Past efforts and current and upcoming initiatives were initially discussed (2022), updates on progress were provided (2023), and broad agreement on resulting action steps was achieved with participants. RESULTS: Summit participants recognized that while much work was ongoing to enhance access to cancer therapeutics globally, communication and synergy across projects and organizations could be enhanced by providing a platform for collaboration and shared expertise. CONCLUSION: The summit resulted in new cross-stakeholder insights and planned collaboration addressing barriers to accessing cancer medications. Specific actions and timelines for implementation and reporting were established.

Action for Increasing Diversity, Market Access, and Capacity in Oncology Registration Trials-Is Africa the Answer? Report From a Satellite Session of the Accelerating Anti-Cancer Agent Development and Validation Workshop.

Patients of African ancestry are not well-represented in cancer clinical trials despite bearing a disproportionate share of mortality both in United States and Africa. We describe key stakeholder perspectives and priorities related to bringing early-stage cancer clinical trials to Africa and outline essential action steps. Increasing Diversity, Market Access, and Capacity in Oncology Registration Trials-Is Africa the Answer? satellite session was organized at 2021 Accelerating Anti-Cancer Agent Development and Validation Workshop. Panelists included representatives of African Organization for Research and Training in Cancer, Uganda Cancer Institute, Uganda Women's Cancer Support Organization, BIO Ventures for Global Health, Bill & Melinda Gates Foundation, the US Food and Drug Administration, Nigeria's National Agency for Food and Drug Administration and Control, Bayer, and Genentech, with moderators from ASCO and American Cancer Society. Key discussion themes and resulting action steps were agreed upon by all participants. Panelists agreed that increasing diversity in cancer clinical trials by including African patients is key to ensuring novel drugs are safe and effective across populations. They underscored the importance of equity in clinical trial access for patients in Africa. Panelists discussed their values related to access and barriers to opening clinical trials in Africa and described innovative solutions from their work aimed at overcoming these obstacles. Multisectoral collaboration efforts that allow leveraging of limited resources and result in sustainable capacity building and mutually beneficial long-term partnerships were discussed as key to outlined action steps. The panel discussion resulted in valuable insights about key stakeholder values and priorities related to bringing early-stage clinical trials to Africa, as well as specific actions for each stakeholder group.

The potential spread of highly pathogenic avian influenza virus via dynamic contacts between poultry premises in Great Britain.

BACKGROUND: Highly pathogenic avian influenza (HPAI) viruses have had devastating effects on poultry industries worldwide, and there is concern about the potential for HPAI outbreaks in the poultry industry in Great Britain (GB). Critical to the potential for HPAI to spread between poultry premises are the connections made between farms by movements related to human activity. Movement records of catching teams and slaughterhouse vehicles were obtained from a large catching company, and these data were used in a simulation model of HPAI spread between farms serviced by the catching company, and surrounding (geographic) areas. The spread of HPAI through real-time movements was modelled, with the addition of spread via company personnel and local transmission. RESULTS: The model predicted that although large outbreaks are rare, they may occur, with long distances between infected premises. Final outbreak size was most sensitive to the probability of spread via slaughterhouse-linked movements whereas the probability of onward spread beyond an index premises was most sensitive to the frequency of company personnel movements. CONCLUSIONS: Results obtained from this study show that, whilst there is the possibility that HPAI virus will jump from one cluster of farms to another, movements made by catching teams connected fewer poultry premises in an outbreak situation than slaughterhouses and company personnel. The potential connection of a large number of infected farms, however, highlights the importance of retaining up-to-date data on poultry premises so that control measures can be effectively prioritised in an outbreak situation.

Operational Strategies for Clinical Trials in Africa.

PURPOSE: In a dramatic reversal of longstanding trends, cancer now kills more Africans than malaria. Despite Africa's growing cancer burden, individuals of African descent, notably those residing in Africa, remain drastically under-represented in cancer clinical trials. Two recent summits-the 1st All Africa Clinical Trial Summit and the Operational Strategy for Clinical Trials in Nigeria Summit-convened experts from governments, the private sector, universities, and professional societies to define the barriers to Africa's participation in multicenter clinical studies and the strategies to eliminate those impedances. METHODS: The discussions held during the two clinical trial summits were condensed into a set of 10 recommendations covering five broad categories (funding, regulation, capacity building, Africa-centric approach, and patient engagement). In this article, four programs are presented as examples of how the summits' recommendations can be put into practice to improve Africa's ability to attract clinical trials, in particular, cancer clinical trials. RESULTS: These example programs all leveraged a multilateral, Africa-driven approach to building Africa's clinical trial capacity, increasing visibility of Africa's current clinical trial capabilities and priorities, improving regulatory infrastructure and enforcement on the continent, and optimizing patient and clinician engagement strategies. CONCLUSION: The four programs are anticipated to catalyze the involvement of more African health care sites in cancer clinical trials, enroll a greater number of African patients with cancer in those trials, and, ultimately, reverse Africa's growing cancer incidence and mortality rates. Each program acts as a blueprint for organizations-whether government, academic, or industry-seeking to address the summits' recommendations and increase Africa's contributions to and active participation in clinical research.

WIPO Re:Search: Catalyzing Public-Private Partnerships to Accelerate Tropical Disease Drug Discovery and Development.

Tropical diseases, including malaria and a group of infections termed neglected tropical diseases (NTDs), pose enormous threats to human health and wellbeing globally. In concert with efforts to broaden access to current treatments, it is also critical to expand research and development (R&D) of new drugs that address therapeutic gaps and concerns associated with existing medications, including emergence of resistance. Limited commercial incentives, particularly compared to products for diseases prevalent in high-income countries, have hindered many pharmaceutical companies from contributing their immense product development know-how and resources to tropical disease R&D. In this article we present WIPO Re:Search, an international initiative co-led by BIO Ventures for Global Health (BVGH) and the World Intellectual Property Organization (WIPO), as an innovative and impactful public-private partnership model that promotes cross-sector intellectual property sharing and R&D to accelerate tropical disease drug discovery and development. Importantly, WIPO Re:Search also drives progress toward the United Nations Sustainable Development Goals (SDGs). Through case studies, we illustrate how WIPO Re:Search empowers high-quality tropical disease drug discovery researchers from academic/non-profit organizations and small companies (including scientists in low- and middle-income countries) to leapfrog their R&D programs by accessing pharmaceutical industry resources that may not otherwise be available to them.

Host-Microbiome Synergistic Control on Sphingolipid Metabolism by Mechanotransduction in Model Arthritis.

Chronic inflammatory autoimmune disorders are systemic diseases with increasing incidence and still lack a cure. More recently, attention has been placed in understanding gastrointestinal (GI) dysbiosis and, although important progress has been made in this area, it is currently unclear to what extent microbiome manipulation can be used in the treatment of autoimmune disorders. Via the use of appropriate models, rheumatoid arthritis (RA), a well-known exemplar of such pathologies, can be exploited to shed light on the currently overlooked effects of existing therapies on the GI microbiome. In this direction, we here explore the crosstalk between the GI microbiome and the host immunity in model arthritis (collagen induced arthritis, CIA). By exploiting omics from samples of limited invasiveness (blood and stools), we assess the host-microbiome responses to standard therapy (methotrexate, MTX) combined with mechanical subcutaneous stimulation (MS) and to mechanical stimulation alone. When MS is involved, results reveal the sphingolipid metabolism as the trait d'union among known hallmarks of (model) RA, namely: Imbalance in the S1P-S1PR1 axis, expansion of Prevotellasp., and invariant Natural Killer T (iNKT)-penia, thus offering the base of a rationale to mechanically modulate this pathway as a therapeutic target in RA.

WIPO Re:Search-A Platform for Product-Centered Cross-Sector Partnerships for the Elimination of Schistosomiasis.

Schistosomiasis is an acute and chronic disease that affects over 200 million people worldwide, and with over 700 million people estimated to be at risk of contracting this disease, it is a pressing issue in global health. However, research and development (R&D) to develop new approaches to preventing, diagnosing, and treating schistosomiasis has been relatively limited. Praziquantel, a drug developed in the 1970s, is the only agent used in schistosomiasis mass drug administration (MDA) campaigns, indicating a critical need for a diversified therapeutic pipeline. Further, gaps in the vaccine and diagnostic pipelines demonstrate a need for early-stage innovation in all areas of schistosomiasis product R&D. As a platform for public-private partnerships (PPPs), the WIPO Re:Search consortium engages the private sector in early-stage R&D for neglected diseases by forging mutually beneficial collaborations and facilitating the sharing of intellectual property (IP) assets between the for-profit and academic/non-profit sectors. The Consortium connects people, resources, and ideas to fill gaps in neglected disease product development pipelines by leveraging the strengths of these two sectors. Using WIPO Re:Search as an example, this article highlights the opportunities for the PPP model to play a key role in the elimination of schistosomiasis.

Contact structures in the poultry industry in Great Britain: exploring transmission routes for a potential avian influenza virus epidemic.

BACKGROUND: The commercial poultry industry in United Kingdom (UK) is worth an estimated 3.4 billion pounds sterling at retail value, producing over 174 million birds for consumption per year. An epidemic of any poultry disease with high mortality or which is zoonotic, such as avian influenza virus (AIV), would result in the culling of significant numbers of birds, as seen in the Netherlands in 2003 and Italy in 2000. Such an epidemic would cost the UK government millions of pounds in compensation costs, with further economic losses through reduction of international and UK consumption of British poultry. In order to better inform policy advisers and makers on the potential for a large epidemic in GB, we investigate the role that interactions amongst premises within the British commercial poultry industry could play in promoting an AIV epidemic, given an introduction of the virus in a specific part of poultry industry in Great Britain (GB). RESULTS: Poultry premises using multiple slaughterhouses lead to a large number of premises being potentially connected, with the resultant potential for large and sometimes widespread epidemics. Catching companies can also potentially link a large proportion of the poultry population. Critical to this is the maximum distance traveled by catching companies between premises and whether or not between-species transmission could occur within individual premises. Premises closely linked by proximity may result in connections being formed between different species and or sectors within the industry. CONCLUSION: Even quite well-contained epidemics have the potential for geographically widespread dissemination, potentially resulting in severe logistical problems for epidemic control, and with economic impact on a large part of the country. Premises sending birds to multiple slaughterhouses or housing multiple species may act as a bridge between otherwise separate sectors of the industry, resulting in the potential for large epidemics. Investment into further data collection and analyses on the importance of industry structure as a determinant for spread of AIV would enable us to use the results from this study to contribute to policy on disease control.

Fostering innovative product development for neglected tropical diseases through partnerships.

Neglected tropical diseases are a group of infectious diseases that threaten and impact a significant portion of individuals living in low- and middle-income countries. Healthcare product R&D, which has been relatively limited for this group of infectious diseases, is timely and requires significant risk and resource investment by companies. Regardless of these costs, the global community has recognized the impact on human health that developing products for these diseases could have. Incentives, including 'push' and 'pull' funding, and platforms that support sharing of intellectual property through partnerships, such as The World Intellectual Property Organization Re:Search, are driving R&D. These mechanisms entice more organizations to participate in global health product development activities, and combine assets and capabilities while reducing costs and risk.

Systemic Wound Healing Associated with local sub-Cutaneous Mechanical Stimulation.

Degeneration is a hallmark of autoimmune diseases, whose incidence grows worldwide. Current therapies attempt to control the immune response to limit degeneration, commonly promoting immunodepression. Differently, mechanical stimulation is known to trigger healing (regeneration) and it has recently been proposed locally for its therapeutic potential on severely injured areas. As the early stages of healing consist of altered intra- and inter-cellular fluxes of soluble molecules, we explored the potential of this early signal to spread, over time, beyond the stimulation district and become systemic, to impact on distributed or otherwise unreachable injured areas. We report in a model of arthritis in rats how stimulations delivered in the subcutaneous dorsal tissue result, over time, in the control and healing of the degeneration of the paws' joints, concomitantly with the systemic activation of wound healing phenomena in blood and in correlation with a more eubiotic microbiome in the gut intestinal district.

Repurposing pharma assets: an accelerated mechanism for strengthening the schistosomiasis drug development pipeline.

Schistosomiasis, one of 17 diseases deemed to be neglected by the World Health Organization, has received little attention from the biopharmaceutical industry. Due to this, only a handful of drugs have been developed to treat schistosomiasis, with only one, praziquantel, used in most endemic regions. Growing concern over resistance coupled with praziquantel's incomplete efficacy across all stages of the Schistosoma platyhelminth life cycle highlights the urgent need for new drugs. The WIPO Re:Search consortium is a platform whereupon biopharmaceutical company compounds are being repurposed to efficiently and cost-effectively develop new drugs for neglected diseases such as schistosomiasis. This article summarizes recent clinical-stage efforts to identify new antischistosomals and highlights biopharmaceutical company compounds with potential for repurposing to treat schistosomiasis.

Long-Term Exposure to Primary Traffic Pollutants and Lung Function in Children: Cross-Sectional Study and Meta-Analysis.

BACKGROUND: There is widespread concern about the possible health effects of traffic-related air pollution. Nitrogen dioxide (NO2) is a convenient marker of primary pollution. We investigated the associations between lung function and current residential exposure to a range of air pollutants (particularly NO2, NO, NOx and particulate matter) in London children. Moreover, we placed the results for NO2 in context with a meta-analysis of published estimates of the association. METHODS AND FINDINGS: Associations between primary traffic pollutants and lung function were investigated in 4884 children aged 9-10 years who participated in the Child Heart and Health Study in England (CHASE). A systematic literature search identified 13 studies eligible for inclusion in a meta-analysis. We combined results from the meta-analysis with the distribution of the values of FEV1 in CHASE to estimate the prevalence of children with abnormal lung function (FEV1<80% of predicted value) expected under different scenarios of NO2 exposure. In CHASE, there were non-significant inverse associations between all pollutants except ozone and both FEV1 and FVC. In the meta-analysis, a 10 µg/m3 increase in NO2 was associated with an 8 ml lower FEV1 (95% CI: -14 to -1 ml; p: 0.016). The observed effect was not modified by a reported asthma diagnosis. On the basis of these results, a 10 µg/m3 increase in NO2 level would translate into a 7% (95% CI: 4% to 12%) increase of the prevalence of children with abnormal lung function. CONCLUSIONS: Exposure to traffic pollution may cause a small overall reduction in lung function and increase the prevalence of children with clinically relevant declines in lung function.

WIPO Re:Search: Accelerating anthelmintic development through cross-sector partnerships.

Neglected tropical diseases (NTDs), malaria, and tuberculosis have a devastating effect on an estimated 1.6 billion people worldwide. The World Intellectual Property Organization (WIPO) Re:Search consortium accelerates the development of new drugs, vaccines, and diagnostics for these diseases by connecting the assets and resources of pharmaceutical companies, such as compound libraries and expertise, to academic or nonprofit researchers with novel product discovery or development ideas. As the WIPO Re:Search Partnership Hub Administrator, BIO Ventures for Global Health (BVGH) fields requests from researchers, identifies Member organizations able to fulfill these requests, and helps forge mutually beneficial collaborations. Since its inception in October 2011, WIPO Re:Search membership has expanded to more than 90 institutions, including leading pharmaceutical companies, universities, nonprofit research institutions, and product development partnerships from around the world. To date, WIPO Re:Search has facilitated over 70 research agreements between Consortium Members, including 11 collaborations focused on anthelmintic drug discovery.

From desk to bed: computational simulations provide indication for rheumatoid arthritis clinical trials.

BACKGROUND: Rheumatoid arthritis (RA) is among the most common human systemic autoimmune diseases, affecting approximately 1% of the population worldwide. To date, there is no cure for the disease and current treatments show undesirable side effects. As the disease affects a growing number of individuals, and during their working age, the gathering of all information able to improve therapies--by understanding their and the disease mechanisms of action--represents an important area of research, benefiting not only patients but also societies. In this direction, network analysis methods have been used in previous work to further our understanding of this complex disease, leading to the identification of CRKL as a potential drug target for treatment of RA. Here, we use computational methods to expand on this work, testing the hypothesis in silico. RESULTS: Analysis of the CRKL network--available at http://www.picb.ac.cn/ClinicalGenomicNTW/software.html--allows for investigation of the potential effect of perturbing genes of interest. Within the group of genes that are significantly affected by simulated perturbation of CRKL, we are lead to further investigate the importance of PXN. Our results allow us to (1) refine the hypothesis on CRKL as a novel drug target (2) indicate potential causes of side effects in on-going trials and (3) importantly, provide recommendations with impact on on-going clinical studies. CONCLUSIONS: Based on a virtual network that collects and connects a large number of the molecules known to be involved in a disease, one can simulate the effects of controlling molecules, allowing for the observation of how this affects the rest of the network. This is important to mimic the effect of a drug, but also to be aware of -and possibly control- its side effects. Using this approach in RA research we have been able to contribute to the field by suggesting molecules to be targeted in new therapies and more importantly, to warrant efficacy, to hypothesise novel recommendations on existing drugs currently under test.

Implications of within-farm transmission for network dynamics: consequences for the spread of avian influenza.

The importance of considering coupled interactions across multiple population scales has not previously been studied for highly pathogenic avian influenza (HPAI) in the British commercial poultry industry. By simulating the within-flock transmission of HPAI using a deterministic S-E-I-R model, and by incorporating an additional environmental class representing infectious faeces, we tracked the build-up of infectious faeces within a poultry house over time. A measure of the transmission risk (TR) was computed for each farm by linking the amount of infectious faeces present each day of an outbreak with data describing the daily on-farm visit schedules for a major British catching company. Larger flocks tended to have greater levels of these catching-team visits. However, where density-dependent contact was assumed, faster outbreak detection (according to an assumed mortality threshold) led to a decreased opportunity for catching-team visits to coincide with an outbreak. For this reason, maximum TR-levels were found for mid-range flock sizes (~25,000-35,000 birds). When assessing all factors simultaneously using multivariable linear regression on the simulated outputs, those related to the pattern of catching-team visits had the largest effect on TR, with the most important movement-related factor depending on the mode of transmission. Using social network analysis on a further database to inform a measure of between-farm connectivity, we identified a large fraction of farms (28%) that had both a high TR and a high potential impact at the between farm level. Our results have counter-intuitive implications for between-farm spread that could not be predicted based on flock size alone, and together with further knowledge of the relative importance of transmission risk and impact, could have implications for improved targeting of control measures.