Genetic diversity of influenza A viruses (IAV) acquired through the error-prone RNA-dependent RNA polymerase (RdRP) or through genetic reassortment enables perpetuation of IAV in humans through ...epidemics or pandemics. Here, to assess the biological significance of genetic diversity acquired through RdRP, we characterize an IAV fidelity variant derived from passaging a seasonal H3N2 virus in the presence of ribavirin, a purine analogue that increases guanosine-to-adenosine mutations. We demonstrate that a single PB1-V43I mutation increases selectivity to guanosine in A/Wuhan/359/95 (H3N2) and A/Vietnam/1203/04 (H5N1) viruses. The H5N1 PB1-V43I-recombinant virus replicates to comparable titres as the wild-type virus in vitro or in the mouse lungs. However, a decrease in viral population diversity at day 3 post inoculation is associated with a tenfold reduced lethality and neurotropism in mice. Applying a fidelity variant with reduced mutational frequency, we provide direct experimental evidence for the role of genetic diversity in IAV pathogenesis.
Biobanks are a critical piece of Research Infrastructure (RI). However, biobanks need to accept the reality of a life cycle for RIs. Until recently, strategies to sustain biobanks have been commonly ...focused on ways to maintain current operational models. However, sustaining biobanks as they exist today may be increasingly challenging in the face of the disruption in health and research priorities caused by the COVID-19 pandemic. In this opinion article, we review the current and emerging future drivers of biobank value for their researchers, institutions, and funders, highlighting utilization and impact of research performed using the biobank as key measures of future value. While biobanks can only indirectly influence the specific impact of the research performed, they can transform themselves to more actively redefine utilization to their advantage. Utilization means more than the balance of samples and data in versus out. Utilization means redirecting expertise to best support end users, and importantly, closing the operating gap between biobanks and their end users who seek to find the right biospecimens and data to pursue their research. We discuss the specific role of locators (those created by public investment) in closing this gap and the need for additional tools for researchers, before and subsequent to connecting with locators. For the former, we specifically propose that more support is needed to assist researchers in the decision as to how to best obtain biospecimens and navigate the options as to whether finding existing biospecimens and data held by a biobank is the optimal solution for a given project, or whether the optimal solution is either contracting with a biobank to collect samples or creating a new biobank. We believe this type of biospecimen navigator platform will help to maximize utilization of current biobank resources, and also promote the services and expertise in biobanks to better serve researchers' needs.
Human health biobanks are forms of research infrastructure that supply biospecimens and associated data to researchers, and therefore juxtapose the activities of clinical care and biomedical ...research. The discipline of biobanking has existed for over 20 years and is supported by several international professional societies and dedicated academic journals. However, despite both rising research demand for human biospecimens, and the growth of biobanking as an academic discipline, many individual biobanks continue to experience sustainability challenges. This commentary will summarize how the COVID-19 pandemic is creating new challenges and opportunities for both the health biobanking sector and the supporting discipline of biobanking. While the challenges for biobanks may be numerous and acute, there are opportunities for both individual biobanks and the discipline of biobanking to embrace change such that biobanks can continue to support and drive biomedical research. We will therefore describe numerous practical steps that individual biobanks and/or the discipline of biobanking can take to survive and possibly thrive in response to the COVID-19 pandemic.
Clinical management of breast cancer is increasingly guided by assessment of tumor phenotypic parameters. One of these is estrogen receptor (ER) status, currently defined by ERα expression. However ...with the discovery of a second ER, ERβ and its variant isoforms, the definition of ER status is potentially more complex. In breast tumors there are two ERβ expression cohorts. One where ERβ is co-expressed with ERα and the other expressing ERβ alone. In the latter subgroup of currently defined ER negative patients ERβ has the potential to be a therapeutic target. Characterization of the nature and role of ERβ in ERα negative tumors is essentially unexplored but available data suggest that the role of ERβ may be different when co-expressed with ERα and when expressed alone. This review summarizes available data and explores the possibility that ERβ signaling may be a therapeutic target in these tumors. Evidence so far supports the idea that the role of ERβ in breast cancer is different in ERα negative compared to ERα positive tumors. However, cohort size and numbers of independent studies are small to date, and more studies are needed with better standardization of antibodies and protocols. Also, the ability to determine the role of ERβ in ERα negative breast cancer and therefore assess ERβ signaling pathways as therapeutic targets would be greatly facilitated by identification of specific downstream markers of ERβ activity in breast cancer.
The promise of precision medicine will only be realized if the healthcare system adapts to meet some key infrastructure needs. Among these needs are adequate biobanking practices, capable of ...producing the biological samples and data that precision medicine relies upon in both the research and clinical phases. Within the research domain, there have been significant improvements to biobanking processes over the past two decades, driven by increased understanding of the impact of pre-analytical variability and the critical role of biospecimen and data quality. In the era of precision medicine, biobanking to support clinical needs has similar quality requirements. The extensive knowledge and resources that have been developed by the research biobanking community are available for adoption by clinical biobanking. The challenge and opportunity now presented to the healthcare system is to adopt or adapt these resources, for example, external biobanking standards and verification programs.
When T cells infiltrate the tumor environment they encounter a myriad of metabolic stressors including hypoxia. Overcoming the limitations imposed by an inadequate tumor vasculature that contributes ...to these stressors may be a crucial step to immune cells mounting an effective anti-tumor response. We sought to determine whether the functional capacity of tumor infiltrating lymphocytes (TIL) could be influenced by the tumor vasculature and correlated this with survival in patients with ovarian cancer.
In 196 high-grade serous ovarian tumors, we confirmed that the tumor vascularity as measured by the marker CD31 was associated with improved patient disease-specific survival. We also found that tumors positive for markers of TIL (CD8, CD4 and forkhead box P3 (FoxP3)) and T cell function (granzyme B and T-cell restricted intracellular antigen-1 (TIA-1)) correlated significantly with elevated vascularity. In vitro, hypoxic CD8 T cells showed reduced cytolytic activity, secreted less effector cytokines and upregulated autophagy. Survival analysis revealed that patients had a significant improvement in disease-specific survival when FoxP3 expressing cells were present in CD31-high tumors compared to patients with FoxP3 expressing cells in CD31-low tumors HR: 2.314 (95% CI 1.049-5.106); p = 0.0377. Patients with high vascular endothelial growth factor (VEGF) expressing tumors containing granzyme B positive cells had improved survival compared to patients with granzyme B positive cells in VEGF-low tumors HR: 2.522 (95% CI 1.097-5.799); p = 0.0294.
Overall, this data provides a rationale for developing strategies aimed at improving the adaptability and function of TIL to hypoxic tumor conditions.
Establishing the importance of biobanking in cancer research is important for research funders and for planning health research infrastructure. This study delineates the importance of biobanking to ...the cancer research landscape in Canada and relative to other forms of health research infrastructure.
The Cancer Research Society (CRS) is a Canadian organization with a broad mission and national portfolio that funds studies across the spectrum of cancer research. We selected all 35 investigators who received CRS grants in the 2010/11 competition and then analyzed their publications from 2010 to 2014. Articles were categorized by overall research area, acknowledged source of funding, specific scientific focus, and the presence of any data that involved an 'indicator' (human biospecimens, cell lines, animal models, advanced microscopy, flow cell sorters, and next generation sequencing) of dependence on different kinds of health research infrastructures. Publications involving biobanking and utilizing biospecimens were further classified by biospecimen provenance and type of biospecimen used.
These investigators generated 502 (from a total of 749) papers that were related to the field of cancer research. Amongst 445 papers that contained primary data, we found no significant differences between CRS funded and 'other funded' papers in terms of biospecimen use, which occurred in 38% of articles. Overall biospecimens were mostly obtained directly from patients (17%), or indirectly from biorepositories (31%) and hospitals (46%). The proportions of studies using other tools was as follows: 54% cell lines, 32% animal models, 14% advanced microscopy, 14% flow sorters, and 8% next generation sequencing. The spectrum of research was very similar to the overall profile of cancer research in Canada in 2010.
This study suggests that biorepositories that coordinate the activity of biobanking rank amongst the most important of established health research infrastructures as contributors to research publications.
Tumor biobanks are a common research infrastructure. As a collection of biospecimens and annotated data collected to support a multitude of research projects, biobanks facilitate access to materials ...that are the critical fuel for the generation of data in up to 40% of cancer research publications. However, quantifying how to measure biobanks' impact and their value on the field of cancer research discoveries and findings, has not been well elucidated.
We have used a qualitative case study approach to illustrate the impact of tumor biobanks. We assessed the impact of three research studies published between 2010 and 2012 that required easily accessible "classic" biobanks. Each study utilized preassembled collections of tumor biospecimens with associated patient outcomes data at the outset of the research project. We compared the resulting journal impact factor, altmetric and field-weighted citation impact factor scores for each article to a set of six "benchmark" articles that represent cancer research and treatment discoveries from the same time period and two sentinel scientific discovery articles.
We developed a value model using a literature search and design-thinking methodologies to illustrate the contributions of these "classic" model biobanks to these research studies. Assessment of the three example articles supported by biobanks demonstrates that the output can have impact that is comparable to the impact of a set of benchmark articles describing milestones in the field of cancer research and cancer care.
These case studies illustrate the value of the sustained investment of funds, planning, time, and effort on the part of the biobanks before the conduct of the research study to be able to ultimately support high-value research. The "value" model will enable further discussion around impact and may be useful in better delineating qualitative metrics of biobank value in the future.
The role of oestrogen receptor (ER) beta in human breast cancer remains unclear. However, it is now apparent that when considering ER beta in human breast cancer it is important to recognise two ER ...beta expressing groups, one in which ER beta is co-expressed with ER alpha and the other where ERbeta is expressed alone. Emerging data support different functions between ER beta when it is expressed alone and when it is co-expressed with ER alpha. With regard to the latter group (ER alpha +/ER beta +), there are now 9 out of 10 retrospective clinical outcome studies published, that support the hypothesis that increased expression of ER beta is associated with increased likelihood of response to endocrine therapy. The data strongly support undertaking prospective studies to determine if the addition of ERbeta to ER alpha is clinically beneficial and whether to include both ER beta and ER alpha when establishing clinically relevant cut-offs for defining ER status.
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