bluuebunny/crossref_metadata_2025_split huggingface dataset:
Should radioiodine now be first line treatment for Graves’ disease?
Authors: Okosieme Onyebuchi E. , Taylor Peter N. , Dayan Colin M. 
Published: March 2020

Abstract
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

AbstractGenome-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

Abstract
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.