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Introduction: It is important for many research stakeholders to know how many biobanks exist. There are several potential data sources that might be expected to provide biobank numbers, such as institutions, research funders, and literature databases (e.g., PubMed), but in practice this information is rarely available and is hard to find. However, the maturation of several online health research biobank locators (also known as directories and catalogs) that relate to 12 countries and/or states has now provided some initial data to address the question of how many health research biobanks exist in relation to population size. Methods: We have analyzed four biobank locators: the Biobanking and Biomolecular Resources Research Infrastructure-European Research Infrastructure Consortium directory, the Canadian Tissue Repository Network locator, the Australian New South Wales Australia Health Pathology locator, and the UK Clinical Research Collaboration Tissue Directory. Results: We conclude that across these locators, and in those regions with potential for high research capacity as indicated by comparable gross domestic products, there are 11-30 health research biobanks/million population (2 large biobanks with >1000 samples and a further 9-28 are medium-small biobanks). Conclusion: Many locators were established primarily to increase utilization of biobanks. However, locators may be more useful in tracking the numbers of biobanks and in assisting funders and institutions to monitor research strategy and prevent unnecessary duplication of biobank resources.

Expression studies have consistently identified tumor protein D52 (TPD52) overexpression in tumor cells. Murine TPD52 (mD52) shares 86% identity with the human orthologue. To study a possible role for TPD52 in transformation, 3T3 fibroblasts were transfected with the full-length cDNA for mD52. Expression of mD52 was confirmed by reverse transcription-PCR (RT-PCR), real-time PCR, and Western blot analysis compared with 3T3 and vector-transfected 3T3 (3T3.V), and the resultant cell line was designated 3T3.mD52. At 4 weeks, 3T3.mD52 gained a 2-fold increase in growth rate, lost contact inhibition, and exhibited a marked phenotype change. Further characterization revealed an acquired ability for anchorage-independent cell growth. To determine whether 3T3.mD52 had become tumorigenic, naïve, healthy, immunocompetent syngeneic mice were inoculated subcutaneously with varying cell doses. Tumors measuring >1 cm2 were detected 60 days postinoculation with 3T3.mD52, and a 50% subcutaneous tumor incidence was obtained with as few as 5 × 105 3T3.mD52 cells. Remarkably, when lungs from 3T3.mD52 tumor-bearing mice were analyzed, numerous tumor nodules were observed, ranging from nodules less than 10 to nodules too numerous to count (inoculation with 1 × 105 and 5 × 106 cells, respectively). Further support for the metastatic capacity of 3T3.mD52 was the demonstration that transforming growth factor (TGF)-βR1 (receptor) expression decreased and TGF-β1 secretion increased in 3T3.mD52 compared with 3T3 controls. cDNA microarray analysis showed a gene expression pattern that further supported mD52-induced transformation and metastasis. Together, these data suggest that mD52 expression in 3T3 cells initiated cellular transformation, tumorigenesis, and progression to metastasis. (Mol Cancer Res 2007;5(2):133–44)

Supplementary Data from Induction of Tumorigenesis and Metastasis by the Murine Orthologue of Tumor Protein D52

Background: 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...

Human gene research studies that describe wrongly identified nucleotide sequence reagents have been mostly identified in journals of low to moderate impact factor, where unreliable findings could be considered to have limited influence on future research. This study examined whether papers describing wrongly identified nucleotide sequences are also published in high impact factor cancer research journals. We manually verified nucleotide sequence identities in originalMolecular Cancerarticles published in 2014, 2016, 2018 and 2020, including nucleotide sequence reagents that were claimed to target circRNAs. Using keywords identified in problematic 2018 and 2020Molecular Cancerpapers, we also verified nucleotide sequence identities in 2020Oncogenepapers that studied miRNA(s) and/or circRNA(s). Overall, 3.8% (253/6,647) and 4.3% (50/1,165) nucleotide sequences that were verified inMolecular CancerandOncogenepapers, respectively, were found to be wrongly identified. These wrongly identified nucleotide sequences were distributed across 18% (92/500) originalMolecular Cancerpapers, including 38%Molecular Cancerpapers from 2020, and 40% (21/52) selectedOncogenepapers from 2020. Original papers with wrongly identified nucleotide sequences were therefore unexpectedly frequent in two high impact factor cancer research journals, highlighting the risks of employing journal impact factors or citations as proxies for research quality.

Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor samples, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty-two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of β-catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.

Human gene research generates new biology insights with translational potential, yet few studies have considered the health of the human gene literature. The accessibility of human genes for targeted research, combined with unreasonable publication pressures and recent developments in scholarly publishing, may have created a market for low-quality or fraudulent human gene research articles, including articles produced by contract cheating organizations known as paper mills. This review summarises the evidence that paper mills contribute to the human gene research literature at scale and outlines why targeted gene research may be particularly vulnerable to systematic research fraud. To raise awareness of targeted gene research from paper mills, we highlight features of problematic manuscripts and publications that can be detected by gene researchers and/or journal staff. As improved awareness and detection could drive the further evolution of paper mill-supported publications, we also propose changes to academic publishing to more effectively deter and correct problematic publications at scale. In summary, the threat of paper mill-supported gene research highlights the need for all researchers to approach the literature with a more critical mindset, and demand publications that are underpinned by plausible research justifications, rigorous experiments and fully transparent reporting.

Refractory cancer-related pain at end-of-life (EoL) is multifaceted and may require utilizing medications with different mechanism of actions beyond opioids. We report the successful use of dexmedetomidine in a 63-year old female with recurrent breast cancer and intractable left arm pain and swelling admitted to University of California, San Diego, Health (UC San Diego Health), palliative care unit. Patient's pain and agitation continued to persist and she declined clinically despite efforts to start methadone, continuous infusion opioids, continuous infusion lidocaine and intravenous chlorpromazine by the palliative care team. On hospital day (HD) 11 patient was started on dexmedetomidine continuous infusion for refractory pain per our protocol at UC San Diego Health. The next day the patient appeared much improved in terms of pain and agitation with grimacing and moaning completely resolved. She was able to have some lucid periods and interacting with her family. With the addition of dexmedetomidine to her pain regiment, the patient was able to peacefully die 5 days later. This case report highlights the clinical utility of demedetomidine in a palliative care unit for refractory pain at EoL.

Cancer therapy related cardiac dysfunction (CTRCD) is an area of increasing focus, particularly during the survivorship period, for paediatric, adolescent and adult cancer survivors. With the advent of immunotherapy and targeted therapy, there is a new set of mechanisms from which paediatric and young adult patients with cancer may suffer cardiovascular injury. Furthermore, cardiovascular disease is the leading cause of morbidity and mortality in the survivorship period. The recently established Australian Cardio-Oncology Registry is the largest and only population-based cardiotoxicity database of paediatric and adolescent and young adult oncology patients in the world, and the first paediatric registry that will document cardiotoxicity caused by chemotherapy and novel targeted therapies using a prospective approach. The database is designed for comprehensive data collection and evaluation of the Australian practice in terms of diagnosis and management of CTRCD. Using the Australian Cardio-Oncology Registry critical clinical information will be collected regarding predisposing factors for the development of CTRCD, the rate of subclinical left ventricular dysfunction and transition to overt heart failure, further research into protectant molecules against cardiac dysfunction and aid in the discovery of which genetic variants predispose to CTRCD. A health economic arm of the study will assess the cost/benefit of both the registry and cardio-oncology clinical implementation. Finally, an imaging arm will establish if exercise cardiac magnetic resonance imaging and VO2 max testing is a more sensitive predictor of cardiac reserve in paediatric and adolescent and young adult oncology patients exposed to cardiac toxic therapies.

Although it is generally accepted that human tissue biobanks are important to facilitate progress in health and medical research, many academic biobanks face sustainability challenges. We propose that biobank sustainability is challenged by a lack of available data describing the outputs and benefits that are produced by biobanks, as reflected by a dearth of publications that enumerate biobank outputs. We further propose that boosting the available information on biobank outputs and using a broader range of output metrics will permit economic analyses such as cost-consequence analyses of biobank activity. Output metrics and cost-consequence analyses can allow biobanks to achieve efficiencies, and improve the quality and/or quantity of their outputs. In turn, biobank output measures provide all stakeholders with explicit and accountable data on biobank value, which could contribute to the evolution of biobank operations to best match research needs, and mitigate some threats to biobank sustainability.

In recent years, it has been proposed that unrealistic requirements for academics and medical doctors to publish in scientific journals, combined with monetary publication rewards, have led to forms of contract cheating offered by organizations known as paper mills. Paper mills are alleged to offer products ranging from research data through to ghostwritten fraudulent or fabricated manuscripts and submission services. While paper mill operations remain poorly understood, it seems likely that paper mills need to balance product quantity and quality, such that they produce or contribute to large numbers of manuscripts that will be accepted for publication. Producing manuscripts at scale may be facilitated by the use of manuscript templates, which could give rise to shared features such as textual and organizational similarities, the description of highly generic study hypotheses and experimental approaches, digital images that show evidence of manipulation and/or reuse, and/or errors affecting verifiable experimental reagents. Based on these features, we propose practical steps that editors, journal staff, and peer reviewers can take to recognize and respond to research manuscripts and publications that may have been produced with undeclared assistance from paper mills.

FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutational status is a pivotal prognosticator in acute myeloid leukemia (AML) patients and significantly increases the risk of disease relapse. However, it remains unclear whether in FLT3-ITD patients referred for allogeneic stem cell transplantation (allo-SCT), baseline cytogenetics significantly impacts clinical outcome. Using the European Society of Blood and Marrow Transplantation registry, we performed a retrospective analysis of 1631 FLT3-ITD AML patients who underwent allo-SCT with the aim of determining the influence of cytogenetic risk category on patient outcomes. Median patient age was 49 years and median follow-up duration was 36 months. Two-year leukemia-free survival (LFS) and incidence of relapse were 54% and 31.6%, respectively. Non-relapse mortality was experienced by 14.4% with a 2-year overall survival (OS) of 60.1%. On multivariate analysis, LFS was significantly lower in patients with intermediate and adverse risk cytogenetics compared with those with favorable risk cytogenetics, (hazard ratio [HR] = 1.48, 95% confidence interval [CI], 1.06-2.06; p = .02), and (HR = 01.65, 95% CI, 1.13-2.40; p = .009), respectively. OS was significantly lower in patients with adverse risk cytogenetics compared with patients with favorable risk cytogenetics (HR = 1.74, 95% CI, 1.16-2.61; p = .008) with a trend toward lower OS in patients with intermediate risk cytogenetics compared to those with favorable risk cytogenetics (HR = 1.43, 95% CI, 1.00-2.05; p = .052). In addition, adverse risk patients and intermediate risk patients experienced higher relapse rates compared with favorable risk patients (HR = 1.83, 95% CI, 1.13-2.94; p = .013 and HR = 1.82, 95% CI, 1.19-2.77; p = .005). Overall, cytogenetic studies aid in refinement of risk stratification in transplanted FLT3-ITD AML patients.

Objectives To study the experiences and views within the health science community regarding the spread and prevention of science misinformation within and beyond the setting of the COVID-19 pandemic. Methods An exploratory study with an empirical ethics approach using qualitative interviews with Australians who produce, communicate and study health science research. Results Key elements that participants considered might facilitate misinformation included: the production of low-quality, fraudulent or biased science research; inadequate public access to high-quality research; insufficient public reading of high-quality research. Strategies to reduce or prevent misinformation could come from within the academic community, academic and lay media publishing systems, government funders and educators of the general public. Recommended solutions from within the scientific community included: rewarding research translation, encouraging standardised study design, increasing use of automated quality assessment tools, mandating study protocol registration, transparent peer review, facilitating wider use of open access and use of newer technologies to target public audiences. There was disagreement over whether preprints were part of the problem or part of the solution. Conclusions There is concern from within the health science community about systemic failings that might facilitate the production and spread of false or misleading science information. We advocate for further research into ways to minimise the production and spread of misinformation about COVID-19 and other science crises in the future.

Aims: The purpose of biobanking is to provide biospecimens and associated data to researchers, yet the perspectives of biobank research users have been under-investigated. This study aimed to ascertain biobank research users' needs and opinions about biobanking services. Methods: An online survey was developed, which requested information about researcher demographics, localities of biobanks accessed, methods of sourcing biospecimens, and opinions on topics including but not limited to, application processes, data availability, access fees, and return of research results. There were 27 multiple choice/check box questions, 4 questions with a 10-point Likert scale, and 8 questions with provision for further comment. A web link for the survey was distributed to researchers in late 2019/early 2020 in four Australian states: New South Wales, Victoria, Western Australia, and South Australia. Results: Respondents were generally satisfied with biobank application processes and the fit for purpose of received biospecimens/data. Nonetheless, most researchers (n = 61/99, 62%) reported creating their own collections owing to gaps in sample availability and a perceived increase in efficiency. Most accessed biobanks (n = 58/74, 78%) were in close proximity (local or intrastate) to the researcher. Most researchers had limited the scope of their research owing to difficulty of obtaining biospecimens (n = 55/86, 64%) and/or data (n = 52/85, 60%), with the top three responses for additional types of data required being "more long term follow up data," "more clinical data," and "more linked government data." The top influence to use a particular biobank was cost, and the most frequently suggested improvement was reduced direct "cost of obtaining biospecimens." Conclusion: Biobanks that do not meet the needs of their end-users are unlikely to be optimally utilized or sustainable. This survey provides valuable insights to guide biobanks and other stakeholders, such as developing marketing and client engagement plans to encourage local research users and discouraging the creation of unnecessary new collections.

We created a petition for a national inquiry into the Australian system of research ethics and governance, to inform the politicians about the problems with the existing system. We analyzed the reasons that signatories offered for why signing the petition was important to them. A total of 409 comments (by 805 signatories) focused on five major themes: (1) views on previous changes to the system of research ethics and governance; (2) drawbacks of the existing system; (3) suggested changes to the system; (4) anticipated impacts of changing the system; and (5) miscellaneous/other comments. Comments ranged from several words to over 400 words in length, and most often focused on the procedural aspects, and commented on theme 2: drawbacks of the existing system.

Nucleotide sequence reagents underpin molecular techniques that have been applied across hundreds of thousands of publications. We have previously reported wrongly identified nucleotide sequence reagents in human research publications and described a semi-automated screening tool Seek & Blastn to fact-check their claimed status. We applied Seek & Blastn to screen >11,700 publications across five literature corpora, including all original publications in Gene from 2007 to 2018 and all original open-access publications in Oncology Reports from 2014 to 2018. After manually checking Seek & Blastn outputs for >3,400 human research articles, we identified 712 articles across 78 journals that described at least one wrongly identified nucleotide sequence. Verifying the claimed identities of >13,700 sequences highlighted 1,535 wrongly identified sequences, most of which were claimed targeting reagents for the analysis of 365 human protein-coding genes and 120 non-coding RNAs. The 712 problematic articles have received >17,000 citations, including citations by human clinical trials. Given our estimate that approximately one-quarter of problematic articles may misinform the future development of human therapies, urgent measures are required to address unreliable gene research articles.

Nucleotide sequence reagents underpin a range of molecular genetics techniques that have been applied across hundreds of thousands of research publications. We have previously reported wrongly identified nucleotide sequence reagents in human gene function publications and described a semi-automated screening tool Seek & Blastn to fact-check the targeting or non-targeting status of nucleotide sequence reagents. We applied Seek & Blastn to screen 11,799 publications across 5 literature corpora, which included all original publications in Gene from 2007-2018 and all original open-access publications in Oncology Reports from 2014-2018. After manually checking the Seek & Blastn screening outputs for over 3,400 human research papers, we identified 712 papers across 78 journals that described at least one wrongly identified nucleotide sequence. Verifying the claimed identities of over 13,700 nucleotide sequences highlighted 1,535 wrongly identified sequences, most of which were claimed targeting reagents for the analysis of 365 human protein-coding genes and 120 non-coding RNAs, respectively. The 712 problematic papers have received over 17,000 citations, which include citations by human clinical trials. Given our estimate that approximately one quarter of problematic papers are likely to misinform or distract the future development of therapies against human disease, urgent measures are required to address the problem of unreliable gene function papers within the literature.Author summaryThis is the first study to have screened the gene function literature for nucleotide sequence errors at the scale that we describe. The unacceptably high rates of human gene function papers with incorrect nucleotide sequences that we have discovered represent a major challenge to the research fields that aim to translate genomics investments to patients, and that commonly rely upon reliable descriptions of gene function. Indeed, wrongly identified nucleotide sequence reagents represent a double concern, as both the incorrect reagents themselves and their associated results can mislead future research, both in terms of the research directions that are chosen and the experiments that are undertaken. We hope that our research will inspire researchers and journals to seek out other problematic human gene function papers, as we are unfortunately concerned that our results represent the tip of a much larger problem within the literature. We hope that our research will encourage more rigorous reporting and peer review of gene function results, and we propose a series of responses for the research and publishing communities.

(1) Background: Genomic precision medicine (PM) utilises people’s genomic data to inform the delivery of preventive and therapeutic health care. PM has not been well-established for use with people of Aboriginal and Torres Strait Islander ancestry due to the paucity of genomic data from these communities. We report the development of a new protocol using co-design methods to enhance the potential use of PM for Aboriginal Australians. (2) Methods: This iterative qualitative study consists of five main phases. Phase-I will ensure appropriate governance of the project and establishment of a Project Advisory Committee. Following an initial consultation with the Aboriginal community, Phase-II will invite community members to participate in co-design workshops. In Phase-III, the Chief Investigators will participate in co-design workshops and document generated ideas. The notes shall be analysed thematically in Phase-IV with Aboriginal community representatives, and the summary will be disseminated to the communities. In Phase-V, we will evaluate the co-design process and adapt our protocol for the use in partnership with other communities. (3) Discussion: This study protocol represents a crucial first step to ensure that PM research is relevant and acceptable to Aboriginal Australians. Without fair access to PM, the gap in health outcome between Aboriginal and non-Aboriginal Australians will continue to widen.

Tumor biobanks have become critical components of the cancer research infrastructure. Consideration of how to place appropriate values on tumor biobanks is important for all stakeholders. At the level of individual biobanks, value is important in determining how to contribute to, utilize, and fund biobanks. At the level of the research system, value is important in determining how to evaluate, rationalize, and sustain or modify the investments in this infrastructure. This review considers approaches and indicators for evaluation of a biobank with a particular focus on utilization, as one important indicator of value, from the perspective of the researcher and funder. The patterns of utilization and the influence of different phases and approaches of research, and types of biobank are described, as well as strategies for biobanks to increase utilization and therefore their value to research.

The capacity of the scientific literature to self-correct is of vital importance, but few studies have compared post-publication journal responses to specific error types. We have compared journal responses to a specific reagent error in 31 human gene knockdown publications, namely a non-targeting or negative control nucleotide sequence that is instead predicted to target a human gene. The 31 papers published by 13 biomedical journals generated 26 published responses (14 retractions, 5 expressions of concern, 7 author corrections which included one resolved expression of concern) as well as 6 stated decisions to take no action. Variations in published responses were noted both between journals and by 4 journals that published different responses to at least 2 papers. A subset of published responses revealed conflicting explanations for the wrongly identified control reagent, despite 30/31 papers obtaining their gene knockdown reagents from the same external supplier. Viewed collectively, different journal responses to human gene knockdown publications with a common reagent error type suggest that editorial staff require more support to interpret post-publication notifications of incorrect nucleotide sequence reagents. We propose a draft template to facilitate the communication, interpretation and investigation of published errors, including errors affecting research reagents.

International audience; The COVID-19 pandemic has thrust preprints into the spotlight, highlighting their advantages and disadvantages. The lack of peer review allows publication to occur with unprecedented speed, but this has raised concerns among biomedical scientists about the quality of the reported research. The study had three primary objectives in regard to COVID-19 preprints: 1. Test the feasibility of automatically and publicly evaluating preprints on a large scale; 2. Assess the prevalence of common quality problems in preprints; and 3. Compare the quality of preprints to published papers. While a substantial fraction (36.2%) of preprints addressed study limitations, the proportion that met other quality criteria was much lower, with only 20% addressing sex as a variable, ~14% sharing open code or data, 7.6% including non-colorblind safe images, and 7.3% showing misleading bar graphs. Both authors and non-authors interacted with the automated Tweets containing reports for preprints. This project shows that it is feasible to conduct large-scale automated screening of preprints for common quality criteria and provide feedback to study authors and readers before publication. These reports can publicly raise awareness about factors that affect study quality and reproducibility, while helping authors to present their research in a more transparent and reproducible manner.

This case-and-commentary examines whether and when prescribers should authorize prescription opioid refills and questions whether and how a patient's living in an area with a high number of overdose deaths should influence that decision. Clinical social work perspectives presented in the commentary inform a multidisciplinary, team-based approach to this decision that is holistic and nondiscriminatory and that prioritizes the ethical value of self-determination.

Seek & Blastn is a semi-automated tool that automatically extracts gene identifiers and nucleotide sequences using named entity recognition techniques. The sentence containing each sequence is automatically analyzed to assign a claimed status (targeting or nontargeting) that is compared with the most likely status according to blastn analysis using the human genomic + transcript database. Subsequently, this tool can be used to identify nucleotide sequence reagent errors in the published or forthcoming scientific literature. The Seek & Blastn tool was developed by Cyril Labbé from the University of Grenoble Alpes, The National Center for Scientific Research (CNRS), Grenoble, France. The authors gratefully acknowledge grant funding from the US Office of Research Integrity, grant ID ORIIR180038-01-00 (awarded to Jennifer Byrne and Cyril Labbé) and the National Health and Medical Research Council of Australia, Ideas grant ID APP1184263 (awarded to Jennifer Byrne, Cyril Labbé and Amanda Capes-Davis). To cite Seek & Blastn or to find further information regarding the tool, please refer to: - Labbé C, Grima N, Gautier T, Favier B, Byrne JA. Semi-automated fact-checking of nucleotide sequence reagents in biomedical research publications: The Seek & Blastn tool. PLoS One. 2019 Mar 1;14(3):e0213266. doi: 10.1371/journal.pone.0213266. PMID: 30822319; PMCID: PMC6396917. For further information regarding this tool: - Byrne, J.A., Labbé, C. Striking similarities between publications from China describing single gene knockdown experiments in human cancer cell lines.Scientometrics 110,1471–1493 (2017). https://doi.org/10.1007/s11192-016-2209-6 - Phillips N. Online software spots genetic errors in cancer papers. Nature. 2017 Nov 20;551(7681):422-423. doi: 10.1038/nature.2017.23003. PMID: 29168818. - Byrne JA, Grima N, Capes-Davis A, Labbé C. The Possibility of Systematic Research Fraud Targeting Under-Studied Human Genes: Causes, Consequences, and Potential Solutions. Biomark Insights. 2019 Feb 5;14:1177271919829162. doi: 10.1177/1177271919829162. PMID: 30783377; PMCID: PMC6366001. - Byrne JA, Christopher J. Digital magic, or the dark arts of the 21stcentury-how can journals and peer reviewers detect manuscripts and publications from paper mills? FEBS Lett. 2020 Feb;594(4):583-589. doi: 10.1002/1873-3468.13747. Epub 2020 Feb 17. PMID: 32067229. - Labbé, C., Cabanac, G., West, R.A.et al. Flagging incorrect nucleotide sequence reagents in biomedical papers: To what extent does the leading publication format impede automatic error detection?.Scientometrics 124,1139–1156 (2020). https://doi.org/10.1007/s11192-020-03463-z

The implementation of cancer surveillance recommendations for childhood cancer patients carrying pathogenic germline variants could lead to earlier detection of disease and improved outcome. In the past, single gene testing was considered for childhood cancer patients with specific tumors where a molecular genetic diagnosis was considered to be of clinical benefit. With the introduction of next-generation sequencing, a growing proportion of childhood cancer patients have been found to carry pathogenic germline variants. The data repositories stemming from these extensive genomic analyses have highlighted areas of discrepancy or discordance between germline genotype and associated malignant phenotype. Aggregation of research data investigating genetic predisposition to childhood cancer should help to address discordant findings by broadening the definitions of childhood cancer predisposition syndromes and identifying new genotype–phenotype associations.

Purpose To mitigate the health risks that result from low health literacy and difficulty identifying patients with insufficient health literacy, health organizations recommend physicians apply health literacy universal precaution communication skills when communicating with all patients. Our aim was to assess how health literacy universal precautions are delivered in routine GP consultations, and explore whether there were differences in how GPs used universal precaution approaches according to areas of deprivation in England. Methods This was a mixed methods study using video and interview data. Ten physicians conducted 217 consultations in primary care settings with adults over 50 years old between July 2017 and March 2018 in England. Eighty consultations (N = 80) met the inclusion criteria of new or persisting problems. Descriptive quantitative analysis of video-recorded consultations using an observation tool and qualitative thematic analysis of transcribed scripts. Meta-themes explored differences in physicians’ communication by areas of deprivation. Results Descriptive statistics showed physicians used a caring tone of voice and attitude (n = 73, 91.3%) and displayed comfortable body language (n = 69, 86.3%) but infrequently demonstrated profession-specific health literacy universal precaution communication skills, such as the teach-back technique (n = 3, 3.8%). Inferences about physicians’ communication from qualitative analysis converged with the quantitative findings. Differences in physicians’ communication varied according to areas of deprivation. Conclusions Physicians need health literacy universal precautions communication skills to improve population health.

Purpose Programmed death-ligand 1 (PD-L1) expression represents a potential predictive biomarker of immune checkpoint blockade response. However, literature about the prevalence of PD-L1 expression in the pediatric cancer setting is discordant. Methods PD-L1 expression was analyzed using immunohistochemistry in 500 pediatric tumors (including neuroblastoma, sarcomas, and brain cancers). Tumors with ≥ 1% cells showing PD-L1 membrane staining of any intensity were scored as positive. Positive cases were further characterized, with cases with weak intensity PD-L1 staining reported as having low PD-L1 expression and cases with a moderate or strong intensity of staining considered to have high PD-L1 expression. Results PD-L1–positive staining was identified in 13% of cases, whereas high PD-L1 expression was found in 3% of cases. Neuroblastoma (n = 254) showed PD-L1 expression of any intensity in 18.9% of cases and was associated with longer overall survival ( P = .045). However, high PD-L1 expression in neuroblastoma (3.1%) was significantly associated with an increased risk of relapse ( P = .002). Positive PD-L1 staining was observed more frequently in low- and intermediate-risk patients ( P = .037) and in cases lacking MYCN amplification ( P = .002). Conclusion In summary, high PD-L1 expression in patients with neuroblastoma may represent an unfavorable prognostic factor associated with a higher risk of cancer relapse. This work proposes PD-L1 immunohistochemical assessment as a novel parameter for identifying patients with an increased likelihood of cancer recurrence.

Zymogen secretory granules in pancreatic acinar cells express two vesicle-associated membrane proteins (VAMP), VAMP2 and -8, each controlling 50% of stimulated secretion. Analysis of secretion kinetics identified a first phase (0–2 min) mediated by VAMP2 and second (2–10 min) and third phases (10–30 min) mediated by VAMP8. Induction of acinar pancreatitis by supramaximal cholecystokinin (CCK-8) stimulation inhibits VAMP8-mediated mid- and late-phase but not VAMP2-mediated early-phase secretion. Elevation of cAMP during supramaximal CCK-8 mitigates third-phase secretory inhibition and acinar damage caused by the accumulation of prematurely activated trypsin. VAMP8−/− acini are resistant to secretory inhibition by supramaximal CCK-8, and despite a 4.5-fold increase in total cellular trypsinogen levels, are fully protected from intracellular trypsin accumulation and acinar damage. VAMP8-mediated secretion is dependent on expression of the early endosomal proteins Rab5, D52, and EEA1. Supramaximal CCK-8 (60 min) caused a 60% reduction in the expression of D52 followed by Rab5 and EEA1 in isolated acini and in in vivo. The loss of D52 occurred as a consequence of its entry into autophagic vacuoles and was blocked by lysosomal cathepsin B and L inhibition. Accordingly, adenoviral overexpression of Rab5 or D52 enhanced secretion in response to supramaximal CCK-8 and prevented accumulation of activated trypsin. These data support that acute inhibition of VAMP8-mediated secretion during pancreatitis triggers intracellular trypsin accumulation and loss of the early endosomal compartment. Maintaining anterograde endosomal trafficking during pancreatitis maintains VAMP8-dependent secretion, thereby preventing accumulation of activated trypsin.

Development of cancer vaccines targeting tumor self-antigens is complex and challenging due to the difficulty of overcoming immune tolerance to self-proteins. Vaccination against tumor self-protein D52 (D52) has been successful, although complete protection appears impaired by immune regulation. Our previous studies suggest that vaccine elicited CD8 + T cells producing interleukin 10 (IL-10) may have a negative impact on tumor protection. Understanding the role CD8+ IL-10 + T cells play in the immune response following vaccination with D52 could result in a more potent vaccine. To address this, we vaccinated IL-10 deficient mice with the murine orthologue of D52; vaccination of wild type (wt) C57BL/6J served as a control for comparison. In separate experiments, D52 vaccinated wt mice were administered IL-10R-specific mAb to neutralize IL-10 function. Interestingly, we observed similar protection against primary tumor challenge in the experimental groups compared to the controls. However, individual IL-10 deficient mice that rejected the primary tumor challenge were re-challenged 140 days post-primary challenge to access vaccine durability and immunologic memory against tumor recurrence. Mice deficient in IL-10 demonstrated a memory response in which 100% of the mice were protected from secondary tumor challenge, while wt mice had diminished recall response (25%) against tumor recurrence. These results with analysis of vaccine-elicited CD8 + T cells for tumor-specific killing and regulatory cell marker expression, add further support to our premise that CD8+ IL-10 + T cells elicited by D52 tumor-self protein vaccine contribute to the suppression of a memory CTL responses and durable tumor immunity.

Background The lungworm, Perostrongylus falciformis (fomerly known as Aelurostrongylus falciformis) has been identified in badgers (Meles meles) in Britain, the Russian Federation, Italy, Norway, Poland, Ukraine, Bosnia Herzegovina and Romania, while Aelurostrongylus pridhami has been reported from badgers in Spain. Results Pulmonary tissue from 1580 Irish badgers was examined and an estimated prevalence of 32.09% (95% CI: 29.79–34.45%) of this parasite was detected. Confirmation of its occurrence was made by PCR analysis on a subset of the population. Conclusion Infestation was widely distributed throughout the Republic of Ireland, with a trend towards higher infestation risk in western versus eastern counties. In addition males were at a higher risk of infestation than females and juveniles were at a significantly higher risk than adult badgers.

Background Genetic testing in children for hereditary cancer predisposition syndromes (CPSs) involves unique psychosocial and family-systems considerations. This retrospective study explored the perspectives and emotional reactions of parents and young adults about cancer-related genetic counseling and testing offered to children in the family. Methods Families were eligible if they had considered genetic testing for a child (≤18 years) within the family. Parents and young adults ≥16 years participated in semistructured interviews that we coded and identified key themes. We also quantitively assessed emotional distress, quality of life, impact of receiving genetic cancer risk information, and service-related satisfaction. Results From 35 interviews (26 parents, nine young adults), we identified themes spanning families' experiences from referral to genetic services to the longer term impact of receiving information about family cancer risk from testing of children. Supported by quantitative data, families generally described positive experiences of genetic services and reported benefits to genetic testing. Nevertheless, families faced unique emotional and relational challenges that changed over the family lifecycle. Those challenges differed according to whether the child was asymptomatic or had a cancer diagnosis at testing. Parents of children with cancer described genetic consultations as a secondary concern to the immediate stressors of their child's treatment. Conclusions We conclude that the successful integration of cancer genetics into pediatric cancer care requires specialist pediatric genetic counseling and psychosocial support services that are able to respond to families' changing needs.

International audience; Nucleotide sequence reagents are verifiable experimental reagents in biomedical publications , because their sequence identities can be independently verified and compared with associated text descriptors. We have previously reported that incorrectly identified nucleotide sequence reagents are characteristic of highly similar human gene knockdown studies, some of which have been retracted from the literature on account of possible research fraud. Because of the throughput limitations of manual verification of nucleotide sequences, we developed a semi-automated fact checking tool, Seek & Blastn, to verify the targeting or non-targeting status of published nucleotide sequence reagents. From previously described and unknown corpora of 48 and 155 publications, respectively, Seek & Blastn correctly extracted 304/342 (88.9%) and 1066/1522 (70.0%) nucleotide sequences and a predicted targeting/ non-targeting status. Seek & Blastn correctly predicted the targeting/ non-targeting status of 293/304 (96.4%) and 988/1066 (92.7%) of the correctly extracted nucleotide sequences. A total of 38/39 (97.4%) or 31/79 (39.2%) Seek & Blastn predictions of incorrect nucleotide sequence reagent use were correct in the two literature corpora. Combined Seek & Blastn and manual analyses identified a list of 91 misidentified nucleotide sequence reagents, which could be built upon through future studies. In summary, incorrect nucleotide sequence reagents represent an under-recognized source of error within the biomedical literature , and fact checking tools such as Seek & Blastn may help to identify papers and manuscripts affected by these errors.

BACKGROUND. There are limited data to predict which novel childhood cancer therapies are likely to be successful. To help rectify this, we sought to identify the factors that impact the success of phase II clinical trials for pediatric malignancies. MATERIALS AND METHODS. We examined the impact of 24 preclinical and trial design variables for their influence on 132 phase II pediatric oncology clinical trials. Success was determined by an objective assessment of patient response, with data analyzed using Fisher's exact test, Pearson's chi‐square test, and logistic regression models. RESULTS. Trials that evaluated patients with a single histological cancer type were more successful than those that assessed multiple different cancer types (68% vs. 47%, 27%, and 17% for 1, 2–3, 4–7, and 8+; p

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.

// Pei Y. Liu 1, * , Nicholas Sokolowski 1, * , Su T. Guo 2, * , Faraz Siddiqi 1 , Bernard Atmadibrata 1 , Thomas J. Telfer 3 , Yuting Sun 1 , Lihong Zhang 1, 4 , Denise Yu 1 , Joshua Mccarroll 1 , Bing Liu 1 , Rui H. Yang 5 , Xiang Y. Guo 5 , Andrew E. Tee 1 , Ken Itoh 6 , Jenny Wang 1, 7 , Maria Kavallaris 1 , Michelle Haber 1 , Murray D. Norris 1, 7 , Belamy B. Cheung 1 , Jennifer A. Byrne 8 , David S. Ziegler 1, 9 , Glenn M. Marshall 1, 9 , Marcel E. Dinger 10, 11 , Rachel Codd 3 , Xu D. Zhang 2, 5 , Tao Liu 1, 7 1 Children’s Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia 2 School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia 3 School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney, Sydney, Australia 4 Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China 5 Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Shanxi, China 6 Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, Hirosaki, Japan 7 Centre for Childhood Cancer Research, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia 8 Children’s Cancer Research Unit, Kids Research Institute, The Children’s Hospital at Westmead, Westmead, Australia 9 Kids Cancer Centre, Sydney Children’s Hospital, High Street, Randwick, Australia 10 Garvan Institute of Medical Research, Darlinghurst, Australia 11 St Vincent’s Clinical School, University of New South Wales Medicine, University of New South Wales Australia, Darlinghurst, Australia * These authors have contributed equally to this work Correspondence to: Tao Liu, email: tliu@ccia.unsw.edu.au Keywords: JQ1, neuroblastoma, quinone-containing compounds, vincristine, nanaomycin Received: June 06, 2016 Accepted: September 28, 2016 Published: October 13, 2016 ABSTRACT BET bromodomain inhibitors are very promising novel anticancer agents, however, single therapy does not cause tumor regression in mice, suggesting the need for combination therapy. After screening a library of 2697 small molecule compounds, we found that two classes of compounds, the quinone-containing compounds such as nanaomycin and anti-microtubule drugs such as vincristine, exerted the best synergistic anticancer effects with the BET bromodomain inhibitor JQ1 in neuroblastoma cells. Mechanistically, the quinone-containing compound nanaomycin induced neuroblastoma cell death but also activated the Nrf2-antioxidant signaling pathway, and the BET bromodomain proteins BRD3 and BRD4 formed a protein complex with Nrf2. Treatment with JQ1 blocked the recruitment of Nrf2 to the antioxidant responsive elements at Nrf2 target gene promoters, and JQ1 exerted synergistic anticancer effects with nanaomycin by blocking the Nrf2-antioxidant signaling pathway. JQ1 and vincristine synergistically induced neuroblastoma cell cycle arrest at the G 2 /M phase, aberrant mitotic spindle assembly formation and apoptosis, but showed no effect on cell survival in normal non-malignant cells. Importantly, co-treatment with JQ1 and vincristine synergistically suppressed tumor progression in neuroblastoma-bearing mice. These results strongly suggest that patients treated with BET bromodomain inhibitors in clinical trials should be co-treated with vincristine.

Objectives Inadequate research biospecimen quality may adversely impact research translation to clinical practice. Despite the development and endorsement of external quality assurance (QA) programs and biospecimen quality reporting tools, there has been little examination of relevant biobank practices. Design and methods An online survey was designed to describe the use and communication of QA and quality control (QC) measures within an Australian cancer biobank cohort (n=21), classified according to access policy. Survey questions examined the development and maintenance of Standard Operating Procedures (SOPs), other specific QA and biospecimen QC activities, and communication of biospecimen QC results to researchers. Results Over three quarters of biobanks utilised regularly-reviewed, best-practice-referenced SOPs, and most biobanks undertook at least one QC activity. Whereas all open-access biobanks (n=11) utilised SOPs and undertook at least one QC activity, these practices were significantly less frequent in restricted-access biobanks (n=10). There were overall low rates of recording the SPREC code, with increased but incomplete recording of Tier 1 BRISQ data. Open-access biobanks were significantly more likely to provide biospecimen QC results to researchers, and to report receiving requests for QC results or additional sample data. Conclusions Improved resourcing and education may be required to boost current levels of QA and QC activities and reporting by cancer biobanks.

Aims and Scope: This editorial announces the new Biomarker Insights Editor-in-Chief. The journal will continue to publish high-quality original reports and review articles in all areas of biomarker research, and will welcome submissions that focus on improving the quality of the biomarker research literature.

There are increasing concerns that research regulatory requirements exceed those required to manage risks, particularly for low- and negligible-risk research projects. In particular, inconsistent documentation requirements across research sites can delay the conduct of multi-site projects. For a one-year, negligible-risk project examining biobank operations conducted at three separate Australian institutions, we found that the researcher time required to meet regulatory requirements was eight times greater than that required for the approved research activity (60 hours versus 7.5 hours respectively). In total, 76 business days (almost four months) were required to obtain the necessary approvals, and site-specific processes required twice as long (52 business days/approximately 10 weeks) as primary Human Research Ethics Committee and Research Governance Office processes (24 business days/ approximately five weeks). We describe the impact of this administrative load on the conduct of a one-year, externally-funded research project, and identify a shared set of application requirements that could be used to streamline and harmonise research governance review of low- and negligible-risk research projects.

Genetic predisposition is an important underlying cause of childhood cancer, although the proportion of patients with childhood cancer carrying predisposing pathogenic germline variants is uncertain. This review considers the pathogenic or likely pathogenic germline variants reported by six studies that used next-generation sequencing to investigate genetic predisposition in selected cohorts of patients with childhood cancer and used incompletely overlapping gene sets for analysis and interpretation. These six studies reported that 8.5%–35.5% of patients with childhood cancer carried clinically relevant germline variants. Analysis of 52 autosomal dominant cancer predisposition genes assumed common to all six studies showed that 5.5%–25.8% of patients with childhood cancer carried pathogenic or likely pathogenic germline variants in at least one of these genes. When only non-central nervous system solid tumours (excluding adrenocortical carcinomas) were considered, 8.5%–10.3% of the patients carried pathogenic or likely pathogenic germline variants in at least one of 52 autosomal dominant cancer predisposition genes. There was a lack of concordance between the genotype and phenotype in 33.3%–57.1% of the patients reported with pathogenic or likely pathogenic germline variants, most of which represented variants in autosomal dominant cancer predisposition genes associated with adult onset cancers. In summary, germline genetic testing in patients with childhood cancer requires clear definition of phenotypes and genes considered for interpretation, with potential to inform and broaden childhood cancer predisposition syndromes.