bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving measurement of harms from others’ drinking: A key informant study on type and severity of harm
Authors: Stanesby Oliver , Gmel Gerhard , Graham Kathryn , Greenfield Thomas K , Waleewong Orratai , Wilsnack Sharon C
Published: March 2020

Aims:

Survey items for measuring harms experienced from others' drinking (AHTO) have been developed primarily to measure type of harm and not severity. However, some type of harms may produce more negative effects than others. We aimed to compare the perceived severity of a comprehensive list of AHTO items to assess consistency in subjective ratings of severity, facilitate a more nuanced analysis and identify strategies to improve measurement of AHTO in epidemiological surveys.

Methods:

Thirty-six leaders of national alcohol surveys (conducted between 1997 and 2016) from 23 countries rated the typical severity of negative effects on the victim of each of 48 types of AHTO using a scale from zero (no negative effect) to 10 (very severe negative effect). The survey leaders were also asked to provide open-ended feedback about each harm and the severity-rating task generally.

Results:

Of 48 harm items, five were classified as extreme severity (mean rating ≥ 8), 17 as high (≥ 6 < 8), 25 as moderate (≥ 4 < 6), and one as low (≤ 4). We used two-way random effects models to estimate absolute agreement intraclass correlation coefficients (AA-ICC) and consistency of agreement intraclass correlation coefficients (CA-ICC). Results showed that there was fair to excellent absolute agreement and consistency of agreement among experts’ ratings of the severity of harms from others’ drinking (single measures CA-ICC = 0.414, single measures AA-ICC = 0.325; average CA-ICC = 0.940, average AA-ICC = 0.914). Harms to children, and harms causing physical, financial, practical, or severe emotional impacts were rated most severe.

Conclusions:

When designing new AHTO surveys and conducting analyses of existing data, researchers should pay close attention to harms with high perceived severity to identify effective ways to prevent severe AHTO and reduce the negative health and social impacts of AHTO. By inquiring into experts' views on survey items, this analysis involves a first scoping of the sort of questions that should be taken into consideration. In-depth analyses of specific sub-sets of harms and qualitative interviews with victims of severe AHTO are likely to help along this work in the future.
The Cryptographic and Metaphysic Nature of Liberatory Pedagogy
Authors: Harris Latashia
Published: March 2020

The initial purpose of this research sought to explore the following: What does it mean and what does it look, function, and feel like for an educational activist of color to fight for the liberation of others, but to also fight for the liberation of themselves? I also questioned and explored how one shares the spirit, metaphysics, and operationalization of liberatory pedagogy without jeopardizing its proliferation in spaces of plausible and probable oppression. In this article, found poetry was developed from participants’ responses and surfaced as a cryptographic method that coded the kinetics of liberatory pedagogy across disciplines.
Copper promotion of myocardial regeneration
Authors: Xiao Ying , Wang Tao , Song Xin , Yang Dan , Chu Qing , Kang Y James
Published: March 2020

Myocardial regeneration is the key to the functional recovery of ischemic heart. Angiogenesis plays a pivotal role in myocardial regeneration by resetting a rejuvenation microenvironment under ischemic conditions. Hypoxia-inducible factor 1 (HIF-1) is the predominant transcription factor in the regulation of angiogenesis. In prolonged myocardial infarction, HIF-1α, the critical subunit of HIF-1, is accumulated in the infarcted myocardium, but fails to activate angiogenesis, suggesting a missing of a critical factor in the HIF-1 regulation of angiogenesis. Copper is involved in multiple steps of HIF-1 regulation of target gene expression. However, copper is deprived during myocardial ischemic injury, leading to deactivation of HIF-1-regulated angiogenesis. Multiple approaches are applied to increasing copper availability in the ischemic heart, effectively reactivating transcription of HIF-1 target angiogenic genes. Copper-induced angiogenesis thus reconstructs the conduit for the transduction of tissue injury signaling, recruitment of tissue repair materials such as stem cells, and the homing of stem cells, leading to the promotion of myocardial regeneration. Thus, copper promotes myocardial regeneration through reactivation of HIF-1-regulated angiogenesis. This would constitute an alternative therapeutic approach to ischemic heart disease.

Impact statement

Copper promotes angiogenesis, but the mechanistic insights have not been fully elucidated until recently. In addition, the significance of copper promotion of angiogenesis in myocardial regeneration was increasingly revealed. Copper critically participates in the regulation of hypoxia-inducible factor 1 (HIF-1) of angiogenic gene expression. Interestingly, myocardial ischemia causes copper efflux from the heart, leading to suppression of angiogenesis, although HIF-1α, the critical subunit of HIF-1, remains accumulated in the ischemic myocardium. Strategies targeting copper specific delivery to the ischemic myocardium lead to selective activation of HIF-1-regulated angiogenic gene expression. Vascularization of the ischemic myocardium re-establishes the tissue injury microenvironment, and rebuilds the conduit for communication between the tissue injury signals and the remote regenerative responses including stem cells. This process promotes myocardial regeneration. Thus, a simple and effective copper supplementation to the ischemic myocardium would become a novel therapeutic approach to the treatment of patients with ischemic heart diseases.
A Cohort Study of Relations Among Caregiver–Infant Co-Occupation and Reciprocity
Authors: Aubuchon-Endsley Nicki L. , Gee Bryan M. , Devine Nancy , Ramsdell-Hudock Heather L. , Swann-Thomsen Hillary , Brumley Michele R.
Published: March 2020

Co-occupation is the mutual engagement of two people in a shared occupation. Recent research has investigated co-occupational activities during sensitive periods to inform clinical practice. However, there remains a dearth of applied research to bridge gaps between research and practice within salient co-occupational relationships between caregivers and infants. The study applied co-occupational constructs of physicality, emotionality, and intentionality within caregiver–infant dyads across infancy. These constructs were examined in relation to caregiver–infant reciprocity in other domains (i.e., language, motor, and affective) to determine the overlapping features of reciprocal co-occupation with established aspects of reciprocity. Results suggest that as infants transitioned into toddlerhood and became more mobile and intentional in behavior, there were observable changes in caregiver–infant reciprocity. Caregiver utterances, affect, touch, and co-occupation were significantly related within and across time, highlighting the need for more studies to disentangle these relations in reference to infant development.
A house divided: The implications of land expropriated during the Napoleonic years—A case study in the Papal States
Authors: Korten Christopher
Published: March 2020

Church-owned lands throughout Europe were confiscated by the French over more than two decades between 1790 and 1814. This action, which became a French financial policy during this period, has been much discussed. We know about the processes undertaken for the transaction of such large-scale sell-offs; we are also familiar with the types of buyers involved in a given region; and we understand the economic results of these sales. However, we have little or no information about what happened to these properties and their owners following the defeat of Napoleon. This article discusses the consequences of land confiscation during the French Revolution and how uniquely the Papal States dealt with problems in relation to the rest of Europe. While most of the affected continent was content to move on and validate the private commercial transactions that had taken place, the papacy, with its hybrid form of government—half-church, half-state—challenged many of these transactions. Former ecclesiastical owners of such lands contested the validity of these sales, mainly purchased by members of the bourgeoisie or the aristocracy. These legal quarrels were acrimonious and created division within the Papal States, the consequences of which have never been considered.
Infrared image segmentation based on multi-information fused fuzzy clustering method for electrical equipment
Authors: Qi Can , Li Qingwu , Liu Yan , Ni Jinyan , Ma Ruxiang , Xu Zheng
Published: March 2020

Serious noise pollution and background interference bring great difficulties to infrared image segmentation of electronic equipment. A novel infrared image segmentation method based on multi-information fused fuzzy clustering method is proposed in this article. Firstly, saliency detection is performed on the infrared image to obtain the saliency map, which determines the initial clustering center and enhances the contrast of the original infrared image. Secondly, the weighting exponent in the objective function is adjusted adaptively. Then local and global spatial constraints are added to the objective function of the fuzzy clustering method, which can reduce the noise and background interference. Finally, the Markov constrained field is calculated according to the initial segmentation result. After that the joint field of fuzzy clustering field and the Markov random field is constructed to obtain the optimized segmentation result. The algorithm is evaluated on the infrared images of electrical equipment, and the experimental results show that the proposed method is robust to noise and complicated background. Compared with other methods, the proposed method improves the average segmentation accuracy and T measure by about 10% and 13%.
An analytical pipeline for identifying and mapping the integration sites of HIV and other retroviruses
Authors: Wells Daria W. , Guo Shuang , Shao Wei , Bale Michael J. , Coffin John M. , Hughes Stephen H. , Wu Xiaolin
Published: March 2020

Background

All retroviruses, including human immunodeficiency virus (HIV), must integrate a DNA copy of their genomes into the genome of the infected host cell to replicate. Although integrated retroviral DNA, known as a provirus, can be found at many sites in the host genome, integration is not random. The adaption of linker-mediated PCR (LM-PCR) protocols for high-throughput integration site mapping, using randomly-sheared genomic DNA and Illumina paired-end sequencing, has dramatically increased the number of mapped integration sites. Analysis of samples from human donors has shown that there is clonal expansion of HIV infected cells and that clonal expansion makes an important contribution to HIV persistence. However, analysis of HIV integration sites in samples taken from patients requires extensive PCR amplification and high-throughput sequencing, which makes the methodology prone to certain specific artifacts.

Results

To address the problems with artifacts, we use a comprehensive approach involving experimental procedures linked to a bioinformatics analysis pipeline. Using this combined approach, we are able to reduce the number of PCR/sequencing artifacts that arise and identify the ones that remain. Our streamlined workflow combines random cleavage of the DNA in the samples, end repair, and linker ligation in a single step. We provide guidance on primer and linker design that reduces some of the common artifacts. We also discuss how to identify and remove some of the common artifacts, including the products of PCR mispriming and PCR recombination, that have appeared in some published studies. Our improved bioinformatics pipeline rapidly parses the sequencing data and identifies bona fide integration sites in clonally expanded cells, producing an Excel-formatted report that can be used for additional data processing.

Conclusions

We provide a detailed protocol that reduces the prevalence of artifacts that arise in the analysis of retroviral integration site data generated from in vivo samples and a bioinformatics pipeline that is able to remove the artifacts that remain.
Brassinosteroid signaling may regulate the germination of axillary buds in ratoon rice
Authors: Xu Huibin , Lian Ling , Wang Fuxiang , Jiang Jiahuan , Lin Qiang , Xie Hongguang , Luo Xi , Zhu Yongsheng , Zhuo Chuanying , Wang Jinlan , Xie Huaan , Jiang Zhaowei , Zhang Jianfu
Published: March 2020

Background

Rice ratooning has traditionally been an important component of the rice cropping system in China. However, compared with the rice of the first harvest, few studies on factors effecting ratoon rice yield have been conducted. Because ratoon rice is a one-season rice cultivated using axillary buds that germinate on rice stakes and generate panicles after the first crop’s harvest, its production is mainly affected by the growth of axillary buds. The objectives of this study were to evaluate the sprouting mechanism of axillary buds to improve the ratoon rice yield.

Results

First, we observed the differentiation and growth dynamics of axillary buds at different nodes of Shanyou 63, and found that they differentiated from bottom to top before the heading of the mother stem, and that they developed very slowly. After heading they differentiated from top to bottom, and the ones on the top, especially the top 2nd node, developed much faster than those at the other nodes. The average length and dry weight of the axillary buds were significantly greater than those at other nodes by the yellow ripe stage, and they differentiated into pistils and stamens by 6 d after the yellow ripe stage. The morphology of vegetative organs from regenerated tillers of Shanyou 63 also suggested the superior growth of the upper buds, which was regulated by hormones, in ratoon rice. Furthermore, a comprehensive proteome map of the rice axillary buds at the top 2nd node before and after the yellow ripe stage was established, and some proteins involved in steroid biosynthesis were significantly increased. Of these, four took part in brassinosteroid (BR) biosynthesis. Thus, BR signaling may play a role in the germination of axillary buds of ratoon rice.

Conclusions

The data provide insights into the molecular mechanisms underlying BR signaling, and may allow researchers to explore further the biological functions of endogenous BRs in the germination of axillary buds of ratoon rice.
Adapting Andersen’s expanded behavioral model of health services use to include older adults receiving long-term services and supports
Authors: Travers Jasmine L. , Hirschman Karen B. , Naylor Mary D.
Published: March 2020

Background

Andersen’s Expanded Behavioral Model of Health Services Use describes factors associated with the use of long-term services and supports (LTSS). This model, however, has only been tested on the intent to use such services among African-American and White older adults and not the actual use. Given the increasing diversity of older adults in the U.S., the ability to conceptualize factors associated with actual use of LTSS across racial/ethnic groups is critical.

Methods

We applied Andersen’s Expanded model in the analysis of 2006–2010 qualitative data using multiple methods to understand both the relevancy of factors for older adults who currently use LTSS vs. those who intend to use LTSS (as described in Andersen’s original exploration). We additionally explored differences in these factors across racial/ethnic groups and included Hispanic older adults in our analyses.

Results

Four additional constructs linked with actual LTSS use emerged: losses and changes, tangible support, capability to provide informal support, and accessibility of informal support. Racial differences were seen in level of participation in decisions to use nursing home services (Not involved: 45% African-Americans vs. 24% Whites). Reports of LTSS use to avoid burdening one’s family were greater among White older adults compared to African-American older adults.

Conclusions

Findings around decision-making and burden along with other constructs enhance our understanding of determinants that influence actual LTSS use and require targeted interventions.
Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone with or without adjuvant chemotherapy in incidentally detected gallbladder carcinoma after simple cholecystectomy or in front of radical resection of BTC (ICC/ECC) – a phase III study of the German registry of incidental gallbladder carcinoma platform (GR)– the AIO/ CALGP/ ACO- GAIN-trial –
Authors: Goetze Thorsten O. , Bechstein Wolf O. , Bankstahl Ulli Simone , Keck Tobias , Königsrainer Alfred , Lang Sven A. , Pauligk Claudia , Piso Pompiliu , Vogel Arndt , Al-Batran Salah-Eddin
Published: March 2020

Background

Currently, complete surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) including Gallbladder Cancer (GBC). Even after curative resection, 5-year OS is only 20–40%. Gallbladder carcinoma is relatively rare, but still the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. Gallbladder carcinoma is suspected preoperatively in only 30% of all pts., while the majority of cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. The encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase of GBC management and even ICC/ECC. Especially because data regarding pure adjuvant chemotherapy in BTC’s are conflicting.

Methods

This is a multicenter, randomized, controlled, open-label phase III study including pts. with incidentally discovered GBCs after simple cholecystectomy in front of radical liver resection and pts. with resectable/ borderline resectable cholangiocarcinomas (ICC/ ECC) scheduled to receive perioperative chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) or surgery alone followed by a therapy of investigator’s choice. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N = 333 patients with GBC or BTC will be included. Recruitment has started in August 2019.

Discussion

The current proposed phase III GAIN study investigates whether induction chemotherapy followed by radical resection in ICC/ECC and re-resection in IGBC (and – if possible – postoperative chemotherapy) prolongs overall survival compared to radical surgery alone for incidental gallbladder carcinoma and primary resectable or borderline resectable cholangiocarcinoma. Utilizing a neoadjuvant approach including a second radical surgery will help to raise awareness for the necessity of radical surgery, especially second radical completion surgery in IGBC and improve the adherence to the guidelines.

Trial registration

ClinicalTrials.gov ID: NCT03673072 from 17.09.2018. EudraCT number: 2017–004444-38 from 02.11.2017.
Addressing critical knowledge and capacity gaps to sustain CRVS system development
Authors: Adair Tim , Richards Nicola , Streatfield Avita , Rajasekhar Megha , McLaughlin Deirdre , Lopez Alan D.
Published: March 2020

Background

Improving civil registration and vital statistics (CRVS) systems requires strengthening the capacity of the CRVS workforce. The improvement of data collection and diagnostic practices must be accompanied by efforts to ensure that the workforce has the skills and knowledge to assess the quality of, and analyse, CRVS data using demographic and epidemiological techniques. While longer-term measures to improve data collection practices must continue to be implemented, it is important to build capacity in the cautious use of imperfect data. However, a lack of training programmes, guidelines and tools make capacity shortages a common issue in CRVS systems. As such, any strategy to build capacity should be underpinned by (1) a repository of knowledge and body of evidence on CRVS, and (2) targeted strategies to train the CRVS workforce.

Main text

During the 4 years of the Bloomberg Philanthropies Data for Health (D4H) Initiative at the University of Melbourne, an extensive repository of knowledge and practical tools to support CRVS system improvements was developed for use by various audiences and stakeholders (the ‘CRVS Knowledge Gateway’). Complementing this has been a targeted strategy to build CRVS capacity in countries that comprised two approaches – in-country or regional training and a visiting Fellowship Program. These approaches address the need to build competence in countries to collect, analyse and effectively use good quality birth and death data, and a longer-term need to ensure that local staff in countries possess the comprehensive knowledge of CRVS strategies and practices necessary to ensure sustainable CRVS development.

Conclusion

The Knowledge Gateway is a dynamic, useful and long-lasting repository of CRVS knowledge for countries and development partners to use to formulate and evaluate CRVS development strategies. Capacity-building through in-country or regional training and the University of Melbourne D4H Fellowship Program will ensure that CRVS capacity and knowledge is developed and maintained, facilitating improvements in CRVS data systems that can be used by policymakers to support better decision-making in health.
Secular trends in testosterone- findings from a large state-mandate care provider
Authors: Chodick Gabriel , Epstein Shdema , Shalev Varda
Published: March 2020

Background

Several studies from the US and Europe have shown a population-level decline in serum testosterone in men from 1970’s to early 2000’s. However, to the best of our knowledge, no study examining population-level decline in testosterone has been published in more recent years. The study objective was therefore to examine secular trends in testosterone levels among Israeli men in the first and second decades of the twenty-first century,

Methods

All incident total testosterone performed between1/2006 and 3/2019 among 102,334 male members of a large health organization.

Results

A significant (p < 0.001) and prominent trend of age-independent decline in the testosterone levels was recorded during the study period for most age groups.

Conclusions

There was a highly significant age-independent decline in total testosterone in the first and second decades of the twenty-first century. The decline was unlikely to be explained by increasing rates of obesity.
Extraction and identification of synovial tissue-derived exosomes by different separation techniques
Authors: Chen Pu , Ruan Anmin , Zhou Jun , Huang Liuwei , Zhang Xiaozhe , Ma Yufeng , Wang Qingfu
Published: March 2020

Objective

The aim of this study is to compare the efficiency of different separation techniques for extracting synovial tissue-derived exosomes.

Methods

The synovial tissue discarded during knee arthroscopy or total knee arthroplasty surgery was collected from the Third Affiliated Hospital of Beijing University of Chinese Medicine. Ultracentrifugation (UC), filtration combined with size exclusion chromatography (SECF), and 8% polyethylene glycol (PEG) were used to extract synovial tissue-derived exosomes. Transmission electron microscopy (TEM), nanoparticle tracer analysis (NTA), and Western Blot (WB) were used to detect the morphology, particle size, and biomarker proteins (CD9, CD63, Flotillin-1, and calnexin) of exosomes.

Results

The extracts of enriched round and discoid vesicles were successfully extracted with UC, SECF, and PEG. The results of TEM have shown that all three extraction methods can extract circular or elliptical vesicles with disc- and cup-shaped structures from the synovial tissue, with the diameter is about 30–150 nm. NTA suggested the main peaks of three groups of exosomes are around 100–120 nm, and the concentration of the three groups of exosomes was greater than 1 × 1010/ml. The results of WB showed that three positive protein markers (CD9, CD63, and Flotillin-1) were highly expressed in the suspension extracted by the three methods and low in the synovial tissue. However, the negative protein (calnexin) was highly expressed in synovial tissues and PEG group, while low in UC and SECF group.

Conclusion

Morphology, particle size, and labeled protein marker detection confirmed that UC, SECF, and PEG can extract exosomes derived from synovial tissue; UC and SECF are more recommended for the extraction of synovial tissue-derived exosomes, which provides a methodological basis for studying the function and mechanism of synovial tissue exosomes in the future.
Should radioiodine now be first line treatment for Graves’ disease?
Authors: Okosieme Onyebuchi E. , Taylor Peter N. , Dayan Colin M.
Published: March 2020

Background

Radioiodine represents a cost-effective treatment option for Graves’ disease. In the UK, it is traditionally reserved for patients who relapse after initial thionamide therapy. In a change from current practice, the new guidelines of the National Institute for Health and Care Excellence (NICE) recommends that radioiodine should now be first line therapy for Graves’ disease. However, the safety of radioiodine with respect to long-term mortality risk has been the subject of recent debate. This analysis examines evidence from treatment related mortality studies in hyperthyroidism and discusses their implications for future Graves’ disease treatment strategies.

Main body

Some studies have suggested an excess mortality in radioiodine treated cohorts compared to the background population. In particular, a recent observational study reported a modest increase in cancer-related mortality in hyperthyroid patients exposed to radioiodine. The interpretation of these studies is however constrained by study designs that lacked thionamide control groups or information on thyroid status and so could not distinguish the effect of treatment from disease. Two studies have shown survival advantages of radioiodine over thionamide therapy, but these benefits were only seen when radioiodine was successful in controlling hyperthyroidism. Notably, increased mortality was associated with uncontrolled hyperthyroidism irrespective of therapy modality.

Conclusions

Early radioiodine treatment will potentially reduce mortality and should be offered to patients with severe disease. However, thionamides are still suitable for patients with milder disease, contraindications to radioiodine, or individuals who choose to avoid permanent hypothyroidism. Ultimately, a patient individualised approach that prioritises early and sustained control of hyperthyroidism will improve long-term outcomes regardless of the therapy modality used.
A benchmark of algorithms for the analysis of pooled CRISPR screens
Authors: Bodapati Sunil , Daley Timothy P. , Lin Xueqiu , Zou James , Qi Lei S.
Published: March 2020

Genome-wide pooled CRISPR-Cas-mediated knockout, activation, and repression screens are powerful tools for functional genomic investigations. Despite their increasing importance, there is currently little guidance on how to design and analyze CRISPR-pooled screens. Here, we provide a review of the commonly used algorithms in the computational analysis of pooled CRISPR screens. We develop a comprehensive simulation framework to benchmark and compare the performance of these algorithms using both synthetic and real datasets. Our findings inform parameter choices of CRISPR screens and provide guidance to researchers on the design and analysis of pooled CRISPR screens.
Mapping evidence on malnutrition screening tools for children under 5 years in sub-Saharan Africa: a scoping review protocol
Authors: Maphosa Tlharihani Phisac , Mulqueeny Delarise Maud , Osei Ernest , Kuupiel Desmond , Mashamba-Thompson Tivani P.
Published: March 2020

Background

In sub-Saharan Africa (SSA), malnutrition remains a major public health challenge, particularly among children under 5 years of age. Despite nutritional screening tools being developed and available to detect early malnutrition in under five-year-old children, malnutrition continues to be a health concern. However, the level of evidence on nutritional screening tools for predicting early malnutrition at the community level in a high disease burden setting is unclear. The objective of this scoping review is to systematically map the evidence on malnutrition screening tools for children under 5 years in sub-Saharan Africa (SSA) and to identify knowledge gaps.

Methods

The proposed study will be guided by an improved Arksey and O’Malley’s framework, Levac et al. 2010 recommendations, and the 2015 Joanna Briggs Institute guidelines. We will conduct a systematic search of relevant imperial sources of evidence from the following databases: CINAHL with full text, Academic search complete via EBSCOhost, Google Scholar, Science Direct, and PubMed. We will search for grey literature from the following humanitarian and aid organization websites: World Health Organization (WHO), The United Nations International Children’s Emergency Fund (UNICEF), and governmental departments. Following the database searches and title screening, eligible sources of evidence will be exported to an EndNote X9 reference library. Thereafter, duplicate articles will be removed in preparation for abstract and full article screenings. Data from the included sources of evidence will be extracted, and the emerging themes will be analyzed. The relationship between the emerging themes and the research questions will be critically examined. The quality of the included sources of evidence will be determined by using the Mixed Method Appraisal Tool (MMAT) version 2018. The search results will be presented in adapted Preferred Reporting Items for Systematic Reviews and Meta-Analysis: Extension for Scoping Reviews chart (PRISMA-ScR).

Discussion

We anticipate finding relevant literature on malnutrition screening tools for children under 5 years in SSA. This study is likely to reveal research gaps, which could guide future research on malnutrition screening tools.
Association of topoisomerase-1 (Topo1) with the efficacy of chemotherapy in a randomized trial for advanced colorectal cancer patients (FOCUS)
Authors: Braun M. S. , Richman S. D. , Adlard J. W. , Daly C. , Turner F. , Barrett J. , Parmar M. , Selby P. , Quirke P. , Seymour M. T.
Published: March 2020

10009

Background: We have assessed potential predictive markers of the efficacy of irinotecan and oxaliplatin in advanced CRC patients randomized to fluorouracil (FU), FU+irinotecan (Ir) or FU+oxaliplatin (Ox). Methods: Pathology specimens were retrieved from 1281 patient in the FOCUS trial (ASCO 05 #3518). Normal and tumor DNA were extracted and tissue microarrays were made for immunohistochemistry (IHC). The following factors were assessed for effect on failure-free survival (FFS) with first-line therapy: IHC for MLH1, MSH2, P53, Topo1, ERCC1, MGMT, and COX2; DNA polymorphisms in GSTP1 (105Val), ABCB1 (C3435T), XRCC1 (Q399R), ERCC2 (K751Q), and UGT1A1*28. Results: Among 823 patients assessable for Topo1 IHC, we observed highly significant heterogeneity (interaction) of treatment effect in relation to Topo1 staining intensity (p=0.008, see table). 489 patients (59%) had moderate or high Topo1 expression; these patients derived highly significant benefit from 1st-line chemotherapy with either Ir or Ox. In contrast, the 334 (41%) patients with low Topo1 IHC expression showed no evidence of benefit from the addition of either Ir or Ox compared with FU alone (HR 1 and 0.9 respectively). When patients receiving FU alone are considered separately, low Topo1 expression was associated with significantly better FFS (HR 0.7 (0.6–0.9)). The other 11 molecular markers showed no significant interactions with treatment received (p values for interaction all > 0.1). Conclusions: We have identified a subgroup of 41% patients (with low Topo1 expression) for whom treatment outcome with FU alone is superior, but who appear to gain no benefit from the addition of Ir or Ox. We believe this to be the first demonstration in a large randomized trial of a genuinely predictive molecular marker. If verified in an independent dataset, this information could be used to select patients who can be safely treated with FU alone, or together with alternative additional agents.

[Table: see text]

No significant financial relationships to disclose.
Alterations in cell proliferation and apoptosis in human colon cancers with microsatellite instability
Authors: Sinicrope F. A. , Garrity M. , Rego R. L. , French A. J. , Foster N. R. , Sargent D. J. , Goldberg R. M. , Laurie J. A. , Burgart L. J. , Thibodeau S. N. , Witzig T. E.
Published: March 2020

10022

Background: Patients with colon cancers displaying high frequency microsatellite instability (MSI-H) are reported to have a favorable prognosis compared to microsatellite stable (MSS) tumors. However, prognostic factors underlying this observation are poorly understood. We studied apoptotic and proliferative indices and their relationship to MSI status, clinicopathological features, and patient survival rates. Methods: Archival Dukes’ stage B2 (n=83) and C (n=246) primary colon adenocarcinomas from patients enrolled in five 5-fluorouracil-based adjuvant therapy trials were analyzed for MSI using a PCR-based assay (MSI-H: ≥30% of loci with instability), and expression of hMLH1, hMSH2 and p53 proteins by immunostaining. Apoptosis was analyzed by the TUNEL assay and the proliferative index (PI: S phase + G2M) and DNA ploidy by flow cytometry. Correlations between markers and associations with overall survival (OS) censored at 8 yrs were sought. Results: MSI-H (n=58.18%) tumors were more likely proximal, diploid, high grade, p53 negative (vs. MSS/MSI-L; all p<0.0001), and from women (p=0.002). Of 58 MSH-H cases tested, 54 showed loss of hMLH1 (n=50) or hMSH2 (n=4) proteins. Median proliferative index (PI) [12.6 vs. 17.4; p=0.0002] was reduced in MSI-H versus MSS/MSI-L tumors. Lower PI was associated with diploidy (p<0.0001) and negative p53 expression (p=0.003). Apoptotic indices (AIs) were increased in MSI-H cancers (vs. MSS/MSI-L, p=0.082), as was the AI/PI ratio (p=0.0065). Interestingly, AI (p=0.02) and AI/PI (p<0.0001) were significantly increased in diploid versus nondiploid tumors, and after removal of MSI-H cases, relationships held for PI and AI/PI with ploidy. Better OS was related to MSI-H (p=0.032), loss of hMLH1 or hMSH2 (p=0.024), diploidy (p=0.0015), and lower PI (p=0.078), but not AI, AI/PI, nor p53 (adjusting for stage, grade, treatment and stratifying by study). Conclusions: MSI-H tumors are characterized by reduced proliferative indices and a higher ratio of apoptosis to proliferation, reflecting slower tumor growth rates compared to MSS/MSI-L tumors. These features may contribute to their better survival. Lower PI and increased AI/PI are also features of diploid MSS cancers.

[Table: see text]
Assessment of tumor suppressor gene methylation for breast cancer risk screening
Authors: Euhus D. , Ashfaq R. , Bu D. , Leitch A. M. , Lewis C.
Published: March 2020

1004

Background: Tumor suppressor gene (TSG) methylation is frequently detected in benign proliferative breast tissue suggesting that it occurs early in breast carcinogenesis. If it can be screen-detected and is associated with breast cancer risk it could be exploited for breast cancer prevention. Methods: Nipple duct lavage (NDL) samples, obtained from 150 women selected to represent a wide range of breast cancer risk, were evaluated by quantitative methylation-specific real time PCR. High risk breasts were defined as those contralateral to a breast cancer (N = 63) and those of women with a 5-year Gail risk ≥ twice the age- and race-matched general population risk (N = 64). The prevelence of TSG methylation and marked atypia was compared for high risk and lower risk breasts using Chi-square. Data for breasts ipsilateral to a breast cancer are shown for comparison, but not included in the calculations for the high risk category. Results: Samples with adequate cellularity were obtained for 219 breasts (76%). The proportion of healthy breasts with ≥ 1% of the gene copies methylated was 13% for Cyclin D2, 19% for APC, 19% for HIN-1, 16% for RASSF1A, and 9% for RAR-beta. RAR-beta provided the best risk discrimination as 15% of high risk breasts were methylated at a level that exceeded the 95th percentile of the lower risk breasts (0.9% of gene copies methylated, P = 0.05). For the table , methylation fractions for all five genes were summed and the threshold for classifying a breast as positive was set to the 95th percentile of the lower risk breasts (methylation sum = 25.0%). Both methylation and marked atypia provide some discrimination between high and lower risk breasts; the combination, however, provides the best discrimination (24% marker positive for high risk versus 9% for lower risk, P = 0.02). Conclusions: TSG methylation in NDL samples is a marker of breast cancer risk that is complementary to cytology.

[Table: see text]

[Table: see text]
Evidence against a role for simian virus 40 in malignant mesothelioma in Japan
Authors: Hiraki A. , Aoe K. , Murakami T. , Toyooka S. , Shivapurkar N. , Gazdar A. , Sueoka N. , Sugi K. , Ueoka H. , Kishimoto T.
Published: March 2020

10040

Background: Malignant mesothelioma is a highly aggressive tumor arising from serosal membranes, most commonly the pleura. Worldwide incidence is increasing because of widespread exposure to asbestos, the major causal agent. Incidence of this disease also is increasing dramatically in Japan. Association of simian virus 40 (SV40) with malignant mesothelioma has been reported, suggesting that SV40 plays an important role in the origin of a subset of these tumors. Most recently, evidence against any role for SV40 in this disease has been also reported. The role of SV40 in malignant mesothelioma remains still controversial. In addition, it has been argued that differences in the reported frequency of SV40 detection in malignant mesothelioma may be related to geographic variation in populations exposed to the virus. Whether SV40 is associated with malignant mesothelioma in Japan therefore is an important issue. However, no study concerning SV40 in malignant mesothelioma has been reported from Japan. Methods: To address this, we studied 35 malignant mesotheliomas including 32 men and 3 women with a median age of 61 years (ranges 34 to 85) and examined the presence of SV40 large T antigen DNA with real time PCR based on TaqMan technology using primers that PCR amplified a specific 156-bp region of the large Tag of SV40 as well as its expression with immnohistological methods using anti-SV40 large T antigen antibody (pAb101, Santa Cruz Biotechnology, Inc., CA). Results: Two of 35 mesotheliomas were considered positive for the presence of SV40 large T antigen DNA, showing ratios of 36.0 and 4.9. The ratio in the positive control was 199.0. The two positive cases consisted of one epithelioid tumor and one biphasic tumor. In addition, none of 35 malignant mesothelioma specimens were positve for staining with SV40 large T antigen antibody; in contrast, diffuse staining for SV40 large T antigen was observed in the cytoplasm and on the cell membranes in the positive control. Conclusions: Taken together, these findings strongly argue against any role of SV40 in the etiology of the majority of malignant mesothelioma in Japan.

No significant financial relationships to disclose.
PD-1/PDL-1 expression in colorectal cancer and its implications for tumor immune evasion
Authors: Gasser M. , Grimm M. , Nichiporuk E. , Bueter M. , Lutz J. , Lebedeva T. , Koenigshausen M. , Thiede A. , Heemann U. , Meyer D. , Waaga-Gasser A.
Published: March 2020

10046

Background: Malignant tumors may evade immunological surveillance by an active downregulation of T cell activation by PD-1 (programmed death 1)/ PDL-1 signaling. This would result in a decreased immune response, thus, promoting tumor growth. Methods: We analyzed the expression of PD-1/PDL-1 genes, cytokines, and T cell subpopulations in tumor tissues of 81 consecutive patients who underwent surgery for primary colorectal cancer according to their UICC stage. Expression of PD-1/PDL-1, T cell subpopulations, and cytokines in tumor tissues were assessed using immunostaining, immunofluorescence, and Real Time PCR. Results: PDL-1 expression on tumor cells was significantly increased, whereas PD-1 expression on tumor cells was decreased at UICC stage III/IV. However, PD-1 expression on infiltrating CD4+ T cells was detectable in patients with advanced tumors whereas PDL-1 expression on CD4+ cells was particularly found at early stages. More regulatory T cells (CD4+CD25+CTLA-4+Foxp3+) were observed in tumors of stage III/IV patients compared to early stages. In addition, a remarkably increased amount of IL-10 was observed in the tumors of UICC III/IV patients. High expression of TGF-ß receptor II in tumors correlated with a progressive course of the disease and tumor relapses, i.e. TGF-ß RII in early tumor stages was indicative for early tumor progress. Conclusions: Our findings indicate that PDL-1 plays a key role during tumor progression and that regulatory T cells are involved in the process of evasion from immune surveillance. The elevated PDL-1 expression on T cells at early tumor stages suggests that PD1/PDL-1 interaction mediates inhibitory signals between T cells enabling the tumor to progress. PDL-1 blockade may prove to be a valuable approach for cancer immunotherapy.

No significant financial relationships to disclose.
Quantification of p16 methylation in serum DNA as a new diagnostic tool for colorectal cancer
Authors: Nakayama G.
Published: March 2020

10050

Background: The incidence of colorectal cancer (CRC), one of the commonest malignancies worldwide, is still increasing. Despite advances in the diagnostic procedure, a large number of patients with CRC still presents with advanced disease. More sensitive and efficient diagnostic technique would make an impact on the prognosis of CRC patients through improving their compliance to the screening program, hence allowing earlier detection of the disease. To test the hypothesis that p16 methylation may serve as a marker for the diagnosis of CRC, we quantified the methylation levels of p16 in the serum DNA of CRC patients. Methods: Fresh specimens of 168 CRC and corresponding noncancerous tissues were obtained surgically at the Department of Surgery II, Nagoya University Graduate School of Medicine, together with the corresponding serum samples obtained 1 week prior to surgery. We defined the p16 methylation rate (p16 MR, in %) as follows: CM/(CM + CU) × 100%. CM is the concentration of methylated p16 sequences and CU is the concentration of unmethylated p16 sequences measured by quantitative methylation-specific PCR (Q-MSP) after bisulfite conversion. The relationship between the p16 MR and clinicopathologic findings were evaluated. Results: Aberrant p16 promoter methylation was found in 59% (99 of 168) of surgically resected CRC tissues. None of the corresponding normal tissues had methylated p16 sequences. 37% (37 of 99) serum samples of the CRC patients with tumoral p16 methylation had the same alterations. p16 MRs of 99 serum samples with tumoral p16 methylation were 0 to 68.9 (mean was 5.43±11.01). p16 MRs were significantly correlated with lymph node metastasis (P=0.001), lymphatic invasion (P=0.001) and venous invasion (P=0.020) of CRCs. p16 MRs increased significantly with tumor stage [stage I : 0.94 ± 1.68, stage II : 2.33 ± 5.19, stage III : 8.49 ± 14.22, stage IV : 10.03 ± 14.27 (P = 0.021)]. Moreover, the survival of patients with low p16 MR was significantly superior to those with high p16 MR (P=0.006). Conclusions: These results suggest that quantification of p16 methylation in the serum DNA might be a novel diagnostic tool and a prognostic factor for CRC.

No significant financial relationships to disclose.
Combinatorial epigenetic treatment approach for hepatocellular carcinoma
Authors: Bitzer M. , Venturelli S. , Armeanu S. , Weiss T. S. , Gregor M. , Lauer U. M.
Published: March 2020

10066

Hepatocellular carcinoma (HCC) displays a striking resistance to chemotherapeutic drugs. Alternative approaches comprise employment of epigenetic compounds such as histone deacetylase inhibitors (HDAC-I) or demethylating agents (DA). Since we could recently demonstrate that HDAC-I exhibit inherent in vitro therapeutic activities against HCC cells, we now explored the potential of a HDAC-I / DA combined epigenetic treatment approach for the highly chemotherapy resistant tumor entity HCC. Methods: HCC cell lines (HepG2, Hep3B, HuH7) and primary human hepatocytes (PHH) were treated with a HDAC-I compound (Suberoylanilide hydroxamic acid - SAHA) together with or without a DA (5-aza-2dC) and examined for cellular damage (enzyme release), proliferation inhibition (SRB), apoptotic cells (FACS), histone acetylation pattern (Western blot) and methylation status (methylation specific PCR). The in vivo activity of our approach was investigated in a HuH7 xenograft mouse hepatoma model. Results: Both SAHA and 5-aza-2dC were found to induce substantial antiproliferative effects and apoptotic cell death in HCC cells; interestingly, combinatorial treatment (SAHA plus 5-aza-2dC) resulted in strongly enhanced anti-HCC effects. Interferences between DA and HDAC-I activities could be excluded by determining both (i) the methylation status of two model genes (p16, SOCS-1; known to be abberantly methylated in HCC) as well as (ii) patterns of histone acetylation. Most importantly, non-malignant primary human hepatocytes (5 different donors) did not exhibit any relevant cellular damage even when high doses of SAHA plus 5-aza-2dC were applied. Finally, in vivo testing of our combinatorial regimen (SAHA plus 5-aza-2dC) was found to be superior in suppression of tumor cell growth when compared to the application of single substances (SAHA or 5-aza-2dC) or placebo. Conclusion: Our combined epigenetic approach in chemotherapy resistant HCC not only has been found to be a highly active treatment option with profound anti-tumor effects both in vitro and in a small animal model in vivo, but did not impair primary human hepatocytes. Thus, this combination therapy now is considered for further investigation in clinical trials.

No significant financial relationships to disclose.