bluuebunny/crossref_metadata_2025_split huggingface dataset:
Employing multiple synchronous outcome samples per subject to improve study efficiency
Authors: A’Hern Roger P. 
Published: October 2021

Abstract
Background
Accuracy can be improved by taking multiple synchronous samples from each subject in a study to estimate the endpoint of interest if sample values are not highly correlated. If feasible, it is useful to assess the value of this cluster approach when planning studies. Multiple assessments may be the only method to increase power to an acceptable level if the number of subjects is limited.

Methods
The main aim is to estimate the difference in outcome between groups of subjects by taking one or more synchronous primary outcome samples or measurements. A summary statistic from multiple samples per subject will typically have a lower sampling error. The number of subjects can be balanced against the number of synchronous samples to minimize the sampling error, subject to design constraints. This approach can include estimating the optimum number of samples given the cost per subject and the cost per sample.

Results
The accuracy improvement achieved by taking multiple samples depends on the intra-class correlation (ICC). The lower the ICC, the greater the benefit that can accrue. If the ICC is high, then a second sample will provide little additional information about the subject’s true value. If the ICC is very low, adding a sample can be equivalent to adding an extra subject. Benefits of multiple samples include the ability to reduce the number of subjects in a study and increase both the power and the available alpha. If, for example, the ICC is 35%, adding a second measurement can be equivalent to adding 48% more subjects to a single measurement study.

Conclusion
A study’s design can sometimes be improved by taking multiple synchronous samples. It is useful to evaluate this strategy as an extension of a single sample design. An Excel workbook is provided to allow researchers to explore the most appropriate number of samples to take in a given setting.
Short-term aspirin and statin chemoprophylaxis did not reduce the risk of developing advanced adenomatous polyps in Black patients
Authors: Renelus Benjamin D. , Dixit Devika , Nguyen Phuong T. , Njoku Kingsley K. , Patel Parth B. , Pintor-Jimenez Katiria , Yan Fengxia , Buscaglia Jonathan M. , Woods Kevin E. , Jamorabo Daniel S. 
Published: October 2021

Abstract
Background
Chemoprevention of colorectal neoplasia with aspirin and statins is under-investigated in Black patients. Since Black patients suffer disproportionately from colon cancer incidence and mortality compared to other populations, we investigated the utility of aspirin and statin in reducing advanced adenomatous polyp (AAP) risk in Black patients.

Methods
We carried out a retrospective cohort study of screening colonoscopies performed at a large urban academic center from 1/1/2011 through 12/31/2019. We analyzed self-identified Black patients with > 1 colonoscopy and no personal history of either inflammatory bowel disease or colon cancer syndromes. Our primary endpoint was first AAP development after index colonoscopy among Black patients taking both aspirin and a statin compared to those taking one or neither medication. We used multivariate logistic regression modeling to investigate our outcomes.

Results
We found data on chemoprophylaxis use in 560 patients. The mean observation period between index colonoscopy and AAP identification was 4 years. AAP developed in 106/560 (19%) of our cohort. We found no difference in AAP risk among Black patients taking both chemoprevention medications compared to partial or no chemoprophylaxis (20% vs 18% respectively, p = 0.49). This finding remained after adjusting for age, body mass index, and tobacco use (odds ratio 1.04, 95% CI 0.65–1.67; p = 0.87).

Conclusions
Short-term aspirin-statin chemoprevention did not reduce the risk of AAP development in our cohort of Black patients. Larger and long-term prospective investigations are needed to investigate the utility of chemoprophylaxis in this population.
Trial Registration: Not applicable.
Tryptophan metabolism induced by TDO2 promotes prostatic cancer chemotherapy resistance in a AhR/c-Myc dependent manner
Authors: Li Fan , Zhao Zhenyu , Zhang Zongbiao , Zhang Yan , Guan Wei 
Published: October 2021

Abstract
Background
Tumor cells exhibit enhanced metabolism of nutrients to satisfy the demand of sustained proliferation in vivo. Seminal reports have presented evidence that tryptophan (Trp) metabolic reprogramming induced by aberrant indoleamine 2,3-dioxygenases could promote tumor development in several cancer types. However, the underlying mechanism of Trp metabolism associated tumor progression is not fully understood.

Materials and methods
Prostatic cell lines LNCaP and VCaP were purchased from the Cell Bank of the Chinese Academy of Sciences (China). Human prostatic tumor tissue samples were obtained from the Tongji Hospital. Female NOD-SCID mice (6 ~ 8 weeks) were purchased from Huafukang Co. (China) and raised in SPF room. Commercial kits and instruments were used for cell apoptosis analysis, real-time PCR, western blotting, ELISA analysis and other experiments.

Result
Comparing the tumor tissues from prostatic cancer patients, we found elevated expression of tryptophan 2, 3-dioxygenase 2 (TDO2), and elevated Trp metabolism in chemo-resistant tumor tissues. In vitro, overexpression of TDO2 significantly promoted the Trp metabolism in prostatic cancer cell lines LNCaP and VCap, resulting in the multidrug resistance development. Mechanistically, we demonstrated that Trp metabolite kynurenine (Kyn) promoted the upregulation and nuclear translocation of transcription factor aryl hydrocarbon receptor (AhR). Subsequently, AhR collaborated with NF-κB to facilitate the activation of c-Myc. In turn, c-Myc promoted the up-regulation of ATP-binding cassette (ABC) transporters and Trp transporters, thereby contributing to chemoresistance and strengthened Trp metabolism in prostatic cancer. Interrupt of Trp/TDO2/Kyn/AhR/c-Myc loop with c-Myc inhibitor Mycro-3 efficiently suppressed the chemoresistance and improved the outcome of chemotherapy, which described a new strategy in clinical prostatic cancer treatment.

Conclusion
Our study demonstrates that elevated TOD2 expression promoted Trp metabolism and metabolite Kyn production, thus resulting in the activation of AhR/c-Myc/ABC-SLC transporters signaling pathway. Interrupt of Trp metabolism/c-Myc loop efficiently suppressed the drugs resistance induced by TDO2, which represented potential target to improve the outcome in drug-resistant prostatic cancer treatment.
The healthy behaviours and COVID-19 mortality among Iranian women: a case–control study
Authors: Pourfarzi Farhad , Rahim Pouran Shima , Dargahi Abdollah , Karami Chiman , Fouladi Nasrin , Zandian Hamed , Zahirian Moghadam Telma 
Published: October 2021

Abstract
Background
Women are among the susceptible groups to Coronavirus disease-19 (COVID-19) in Ardabil, north-west of Iran, despite the current global status. The underlying causes of high incidence and fatality rate of women in Ardabil are not fully understood. Hence, this study aimed to investigate the healthy behaviours in women of Ardabil and its relationship with COVID-19 mortality.

Methods
We conducted a case–control study to compare the adherence to health protocols and behaviours with respect to COVID-19 between the infected (261 patients) and healthy (515 persons) women. Health protocols and behaviours such as using mask, gloves, disinfectants, history of travelling and contacting, and attending various gatherings and places during the COVID-19 pandemic along with demographic variables were defined as independent variables, and COVID-19 death rate was defined as the dependent variable. Multivariable logistic regression methods were used to explore the risk factors associated with COVID-19 mortality.

Results
Chi-square and Fisher tests showed significant differences between infected and healthy women in terms of history of contact and traveling (p < 0.05), wearing mask (p < 0.001), going to work place (p < 0.001), and attend public gatherings (p = 0.038). Multivariable logistic regression disclosed that the age group over 80 years: 8.97 times (95% CI 2.27–29.85), women with underlying chronic diseases: 4.14 times (95% CI 1.61–10.64), and obese women: 3.01 times (95% CI 1.04–6.03) were more likely to die from COVID-19 than other women.

Conclusion
Considering the high incidence and mortality rate in Ardabil women due to COVID-19 and the corresponding health behavioural factors, special emphasis should be given to the increase of women awareness on the importance of healthy behaviours, diet, and life-style.
Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway
Authors: Wu Zhengzhong , Yan Leye , Lin Junqing , Ke Kun , Yang Weizhu 
Published: October 2021

AbstractBackgroundIncreased tryptophan (Trp) metabolism by indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase (TDO) represents one of the most studied pathways for immunosuppression in tumor tissues. However, the pro-tumor effects induced by Trp metabolism remain controversial.MethodsThe paraffin sections of tumor tissues were obtained from patients with liver cancer and examined by immunohistochemical staining to investigate the role of Trp metabolic enzymes. To further confirm the pro-tumor effects induced by TDO2, we established TDO2 overexpression SMC-7721 and HepG2 liver cancer cell lines, and western blotting, cell proliferation, and colony formation were evaluated. Meanwhile, liver cancer subcutaneous mice models were established, and the tumorigenic rates of SMC-7721 cells, tumor volume and survival of bearing mice were calculated. In addition, the survival data of liver cancer patients from The Cancer Genome Atlas (TCGA) database were downloaded to analyze the effect of TDO2 expression on the survival of patients with liver cancer.ResultsHere, we showed that constitutive TDO2 expression gave rise to liver cancer through upregulation of Trp metabolism. And the TDO2 expression was positively correlated with the poor prognosis in liver cancer patients. TDO2 expression in tumor cells accounted for the release of kynurenine (Kyn), which activated aryl hydrocarbon receptor (AhR) to promote liver cancer cells proliferation. Mechanistically, we found that AhR expression contributed to the secretion of Interleukin-6 (IL-6), thereby promoting tumor cells proliferation through the STAT3 and NF-kB/TIM4 signals. Interrupt of AhR signals by PDM2 revealed improved outcomes in subcutaneous tumor-bearing mice.ConclusionsTogether, our study showed that the TDO2/Kyn/AhR/IL-6 signaling pathway was a novel mechanism underlying the malignancy of liver cancer, and suggested that AhR signals might be a valuable therapeutic target for tumor therapy.
Purification of native histidine-rich protein 2 (nHRP2) from Plasmodium falciparum culture supernatant, infected RBCs, and parasite lysate
Authors: Singh Balwan , McCaffery Jessica N. , Kong Amy , Ah Yong , Wilson Scott , Chatterjee Sayan , Tomar Deepak , Aidoo Michael , Udhayakumar Venkatachalam , Rogier Eric 
Published: October 2021

Abstract
Background
Despite the widespread use of histidine-rich protein 2 (HRP2)-based rapid diagnostic tests (RDTs), purified native HRP2 antigen is not standardly used in research applications or assessment of RDTs used in the field.

Methods
This report describes the purification of native HRP2 (nHRP2) from the HB3 Plasmodium falciparum culture strain. As this culture strain lacks pfhrp3 from its genome, it is an excellent source of HRP2 protein only and does not produce the closely-related HRP3. The nHRP2 protein was isolated from culture supernatant, infected red blood cells (iRBCs), and whole parasite lysate using nickel-metal chelate chromatography. Biochemical characterization of nHRP2 from HB3 culture was conducted by SDS-PAGE and western blotting, and nHRP2 was assayed by RDT, ELISA, and bead-based immunoassay.

Results
Purified nHRP2 was identified by SDS-PAGE and western blot as a − 60 kDa protein that bound anti-HRP-2 monoclonal antibodies. Mouse anti-HRP2 monoclonal antibody was found to produce high optical density readings between dilutions of 1:100 and 1:3,200 by ELISA with assay signal observed up to a 1:200,000 dilution. nHRP2 yield from HB3 culture by bead-based immunoassay revealed that both culture supernatant and iRBC lysate were practical sources of large quantities of this antigen, producing a total yield of 292.4 µg of nHRP2 from two pooled culture preparations. Assessment of nHRP2 recognition by RDTs revealed that Carestart Pf HRP2 and HRP2/pLDH RDTs detected purified nHRP2 when applied at concentrations between 20.6 and 2060 ng/mL, performing within a log-fold dilution of commercially-available recombinant HRP2. The band intensity observed for the nHRP2 dilutions was equivalent to that observed for P. falciparum culture strain dilutions of 3D7 and US06 F Nigeria XII between 12.5 and 1000 parasites/µL.

Conclusions
Purified nHRP2 could be a valuable reagent for laboratory applications as well as assessment of new and existing RDTs prior to their use in clinical settings. These results establish that it is possible to extract microgram quantities of the native HRP2 antigen from HB3 culture and that this purified protein is well recognized by existing monoclonal antibody lines and RDTs.

Graphical Abstract
Generating evidence on the use of Image and performance enhancing drugs in the UK: results from a scoping review and expert consultation by the Anabolic Steroid UK network
Authors: McVeigh Jim , Hearne Evelyn , Boardley Ian , Bates Geoff , Hope Vivian , Ralphs Rob , Van Hout Marie Claire 
Published: October 2021

AbstractBackgroundThe use of anabolic androgenic steroids (AAS) and associated image and performance enhancing drugs (IPEDs) is now a global phenomenon. There is a need to develop evidence to support the development of interventions to prevent the commencement of use, to minimise the potential harms or to support those in their cessation of use. While the United Kingdom (UK) is no exception to this issue, its public health and legislative response to the phenomenon differs to other countries and requires the examination of research specific to the UK. Therefore, a scoping review has been conducted to examine the recent relevant literature to help inform the development and evaluation of effective interventions to reduce the harmful use of IPEDs.MethodsA comprehensive search strategy was developed for multiple bibliographic databases, supported by and iterative citation searching process and complimented by expert input from the Anabolic Steroid UK Network. Research conducted by or UK academics or within the UK were eligible, if published in the previous five years.ResultsIn total 87 eligible outputs were identified, including 26 review articles, 25 qualitative papers and 24 quantitative papers. together with small numbers of clinical studies/case reports (6) and commentaries/correspondence (6). The most common topics of research were public health, treatment and harm reduction (41), followed by studies focusing on epidemiology, sub-groups of people using IPEDs and motivations for use (34). The studies illustrated the diverse populations of people who use a range of enhancement drugs including concomitant psychoactive drug use. A number of papers focused on blood borne viruses and associated issues, while others reported on the uptake of needle and syringe programmes. No effectiveness evaluations related to any aspect of treatment, harm reduction or other intervention were published during study period.ConclusionThere is a need for the development of effectiveness evaluations of current interventions and any future service provision for people using image and performance enhancing drugs. While there have been no studies of this nature to date, this review illustrates the rich data that has been gathered through diverse methodologies, that will assist in the development of future effectiveness evaluations.
MiR-144-3p inhibits gastric cancer progression and stemness via directly targeting GLI2 involved in hedgehog pathway
Authors: Lu Yixun , Zhang Benlong , Wang Baohua , Wu Di , Wang Chuang , Gao Yunhe , Liang Wenquan , Xi Hongqing , Wang Xinxin , Chen Lin 
Published: October 2021

Abstract
Background
Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide. Due to the dismal prognosis, identifying novel therapeutic targets in GC is urgently needed. Evidences have shown that miRNAs played critical roles in the regulation of tumor initiation and progression. GLI family zinc finger 2 (GLI2) has been reported to be up-regulated and facilitate cancer progression in multiple malignancies. In this study, we focused on identifying GLI2-targeted miRNAs and clarifying the underlying mechanism in GC.

Methods
Paired fresh gastric cancer tissues were collected from gastrectomy patients. GLI2 and miRNAs expression were detected in gastric cancer tissues and cell lines. Bioinformatics analysis was used to predict GLI2-targeted miRNAs and dual-luciferase reporter assay was applied for target verification. CCK-8, clone formation, transwell and flow cytometry were carried out to determine the proliferation, migration, invasion and cell cycle of gastric cancer cells. Tumorsphere formation assay and flow cytometry were performed to detail the stemness of gastric cancer stem cells (GCSCs). Xenograft models in nude mice were established to investigate the role of the miR-144-3p in vivo.

Results
GLI2 was frequently upregulated in GC and indicated a poor survival. Meanwhile, miR-144-3p was downregulated and negatively correlated with GLI2 in GC. GLI2 was a direct target gene of miR-144-3p. MiR-144-3p overexpression inhibited proliferation, migration and invasion of gastric cancer cells. Enhanced miR-144-3p expression inhibited tumorsphere formation and CD44 expression of GCSCs. Restoration of GLI2 expression partly reversed the suppressive effect of miR-144-3p. Xenograft assay showed that miR-144-3p could inhibit the tumorigenesis of GC in vivo.

Conclusions
MiR-144-3p was downregulated and served as an essential tumor suppressor in GC. Mechanistically, miR-144-3p inhibited gastric cancer progression and stemness by, at least in part, regulating GLI2 expression.
Comprehensive analysis of oncogenic fusions in mismatch repair deficient colorectal carcinomas by sequential DNA and RNA next generation sequencing
Authors: Wang Jing , Li Ruiyu , Li Junjie , Yi Yuting , Liu Xiaoding , Chen Jingci , Zhang Hui , Lu Junliang , Li Cami , Wu Huanwen , Liang Zhiyong 
Published: October 2021

Abstract
Background
Colorectal carcinoma (CRC) harboring oncogenic fusions has been reported to be highly enriched in mismatch repair deficient (dMMR) tumors with MLH1 hypermethylation (MLH1me+) and wild-type BRAF and RAS. In this study, dMMR CRCs were screened for oncogene fusions using sequential DNA and RNA next generation sequencing (NGS).

Results
Comprehensive analysis of fusion variants, genetic profiles and clinicopathological features in fusion-positive dMMR CRCs was performed. Among 193 consecutive dMMR CRCs, 39 cases were identified as MLH1me+BRAF/RAS wild-type. Eighteen fusion-positive cases were detected by DNA NGS, all of which were MLH1me+ and BRAF/RAS wild-type. RNA NGS was sequentially conducted in the remaining 21 MLH1me+BRAF/RAS wild-type cases lacking oncogenic fusions by DNA NGS, and revealed four additional fusions, increasing the proportion of fusion-positive tumors from 46% (18/39) to 56% (22/39) in MLH1me+BRAF/RAS wild-type dMMR cases. All 22 fusions were found to involve RTK-RAS pathway. Most fusions affected targetable receptor tyrosine kinases, including NTRK1(9/22, 41%), NTRK3(5/22, 23%), ALK(3/22, 14%), RET(2/22, 9%) and MET(1/22, 5%), whilst only two fusions affected mitogen-activated protein kinase cascade components BRAF and MAPK1, respectively. RNF43 was identified as the most frequently mutated genes, followed by APC, TGFBR2, ATM, BRCA2 and FBXW7. The vast majority (19/22, 86%) displayed alterations in key WNT pathway components, whereas none harbored additional mutations in RTK-RAS pathway. In addition, fusion-positive tumors were typically diagnosed in elder patients and predominantly right-sided, and showed a significantly higher preponderance of hepatic flexure localization (P < 0.001) and poor differentiation (P = 0.019), compared to fusion-negative MLH1me+ CRCs.

Conclusions
We proved that sequential DNA and RNA NGS was highly effective for fusion detection in dMMR CRCs, and proposed an optimized practical fusion screening strategy. We further revealed that dMMR CRCs harboring oncogenic fusion was a genetically and clinicopathologically distinctive subgroup, and justified more precise molecular subtyping for personalized therapy.
Moving for safety: a qualitative analysis of affected communities’ evacuation response during the 2014 Mayon Volcano eruption
Authors: Martinez-Villegas Ma. Mylene , Solidum Renato U. , Saludadez Jean A. , Pidlaoan Abigail C. , Lamela Ruben C. 
Published: October 2021

AbstractThis study looks at the 2014 Mayon Volcano eruption to identify possible factors that contribute to the actions that people (local authorities/officials, community leaders, and residents) take during an eruptive period. We used qualitative analysis to examine interviews of people who experienced the August–December 2014 Mayon Volcano unrest, to determine the nature of people’s understanding of hazards and risks, their decision-making, and response process. The thematic analysis shows that residents reacted to the information given to them in several ways- they evacuated when ordered (mandatory), chose not to evacuate for various reasons (e.g. they did not believe they are in danger citing experiences, inconvenience in evacuation sites, etc.), and evacuated even when not ordered to (voluntary). The local officials and community leaders were asked about their views on the possible reasons or motivations as to why residents would evacuate, and common themes that emerged were fear emanating from the experience of past eruptions, obeying the order to evacuate because it is the law, and order from provincial authorities (setting aside personal opinion on the state of the volcano based on experiential knowledge), and the potential to receive relief goods for those who are economically in need. This paper also looks at the challenges to local officials when an eruptive episode occurs- but the event falls short of the expected typical explosive behavior from the volcano. This study argues for people’s experiential knowledge as an important factor in shaping views about hazards and risks that leads to the decision-making of individuals and its importance in risk communication strategies.