bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving expression and assembly of difficult-to-express heterologous proteins in Saccharomyces cerevisiae by culturing at a sub-physiological temperature
Authors: So Kum-Kang , Le Ngoc My Tieu , Nguyen Ngoc-Luong , Kim Dae-Hyuk
Published: March 2023

Background

Escherichia coli heat labile toxin B subunit (LTB) is one of the most popular oral vaccine adjuvants and intestine adsorption enhancers. It is often expressed as a fusion partner with target antigens to enhance their immunogenicity as well as gut absorbability. However, high expression levels of a fusion protein are critical to the outcome of immunization experiments and the success of subsequent vaccine development efforts. In order to improve the expression and functional assembly of LTB-fusion proteins using Saccharomyces cerevisiae, we compared their expression under culture conditions at a sub-physiological temperature 20 °C with their expression under a standard 30 °C.

Results

The assembled expression of LTB-EDIII2(LTB fused to the envelope domain III (EDIII) of Dengue virus serotype 2), which was expressed at the level of 20 µg/L in our previous study, was higher when the expression temperature was 20 °C as opposed to 30 °C. We also tested whether the expression and functional assembly of a difficult-to-express LTB fusion protein could be increased. The assembled expression of the difficult-to-express LTB-VP1 fusion protein (LTB fused to VP1 antigen of Foot-and-Mouth Disease Virus) dramatically increased, although the total amount of expressed protein was still lower than that of LTB-EDIII2. Slight but significant increase in the expression of well-known reporter protein eGFP, which has previously been shown to be increased by cultivation at 20 °C, was also observed in our expression system. As no significant changes in corresponding transcripts levels and cell growth were observed between 20 °C and 30 °C, we infer that translation and post-translational assembly are responsible for these enhancements.

Conclusions

The effects of lowering the expression temperature from 30 °C to 20 °C on protein expression and folding levels inS. cerevisiae, using several proteins as models, are reported. When heterologous proteins are expressed at 20 °C, a greater amount of (specially, more assembled) functional proteins accumulated than at 30 °C. Although further studies are required to understand the molecular mechanisms, our results suggest that lowering the expression temperature is a convenient strategy for improving the expression of relatively complexly structured and difficult-to-express proteins inS. cerevisiae.
Six immune-related promising biomarkers may promote hepatocellular carcinoma prognosis: a bioinformatics analysis and experimental validation
Authors: Lin Xia-Hui , Li Dong-ping , Liu Zhi-Yong , Zhang Si , Tang Wen-qing , Chen Rong-xin , Weng Shu-qiang , Tseng Yu-jen , Xue Ru-yi , Dong Ling
Published: March 2023

Background

Abnormal miRNA and mRNA expression and dysregulated immune microenvironment have been found to frequently induce the progression of hepatocellular carcinoma (HCC) in recent reports. In particular, the immune-related competing endogenous RNAs (ceRNA) mechanism plays a crucial role in HCC progression. However, the underlying mechanisms remain unclear.

Methods

Differentially expressed immune-related genes were obtained from the Immport, GEO, and TCGA databases. The mRNA and protein expression levels in HCC tissues and adjacent normal tissues were confirmed, and we further investigated the methylation levels of these biomarkers to explore their function. Then, the TIMER and TISCH databases were used to assess the relationship between immune infiltration and hub genes. Survival analysis and univariate and multivariate Cox models were used to evaluate the association between hub genes and HCC diagnosis. Hub gene expression was experimentally validated in six HCC cell lines and 15 HCC samples using qRT-PCR and immunohistochemistry. The hub genes were uploaded to DSigDB for drug prediction enrichment analysis.

Results

We identified that patients with abnormal miRNAs (hsa-miR-125b-5p and hsa-miR-21-5p) and their targeted genes (NTF3, PSMD14, CD320, and SORT1) had a worse prognosis. Methylation analysis of miRNA-targeted genes suggested that alteration of methylation levels is also a factor in the induction of tumorigenesis. We also found that the development of HCC progression caused by miRNA-mRNA interactions may be closely correlated with the infiltration of immunocytes. Moreover, the GSEA, GO, and KEGG analysis suggested that several common immune-related biological processes and pathways were related to miRNA-targeted genes. The results of qRT-PCR, immunohistochemistry, and western blotting were consistent with our bioinformatics results, suggesting that abnormal miRNAs and their targeted genes may affect HCC progression.

Conclusions

Briefly, our study systematically describes the mechanisms of miRNA-mRNA interactions in HCC and predicts promising biomarkers that are associated with immune filtration for HCC progression.
The comparison of long-term oncological outcomes and complications after proximal gastrectomy with double tract reconstruction versus total gastrectomy for proximal gastric cancer
Authors: Ying Keming , Bai Weisong , Yan Guiru , Xu Ziseng , Du Shenheng , Dang Chengxue
Published: March 2023

Background

Conventional methods for treating patients with proximal gastric cancer (PGC) include proximal gastrectomy (PG) and total gastrectomy (TG) and such methods have become challenging due to double tract reconstruction (DTR). However, the clinical outcomes remain unclear. This study was performed with the aim of verifying that PG-DTR was beneficial in terms of reducing the incidence of postoperative complications and improving the prognosis.

Methods

The PGC patient cohort was retrospectively grouped into the PG-DTR and TG groups. Clinicopathological features, complications, and survival data were compared between the two groups.

Results

A total of 388 patients were included in the analyses. Patients who were subjected to TG tended to have more severe gastroesophageal reflux (GR) (P = 0.041), anemia (P = 0.007), and hypoalbuminemia (P < 0.001). Overall survival rates, regardless of clinical stage, were significantly different between the PG-DTR and TG groups (all P < 0.05). The multivariate Cox regression analysis confirmed that surgical procedure, tumor size, infiltration depth, lymph node metastasis, differentiation, and age were independent risk factors. The patients were likely to benefit from PG-DTR (all HR > 1 and P < 0.05). However, no significant differences were observed in the risks of GR, anemia, and hypoalbuminemia (all P > 0.05). Moreover, the nomogram derived from significant parameters showed great calibration and discrimination ability and significant clinical benefit.

Conclusions

The patients who underwent PG-DTR had a favorable prognosis. The risk of postoperative complications, such as severe GR, anemia, and hypoalbuminemia, was lower in PG-DTR than in TG. Thus, PG-DTR is more beneficial for patients with PGC and may be a valuable and promising surgical procedure.
Quality of care in the context of universal health coverage: a scoping review
Authors: Yanful Bernice , Kirubarajan Abirami , Bhatia Dominika , Mishra Sujata , Allin Sara , Di Ruggiero Erica
Published: March 2023

Introduction

Universal health coverage (UHC) is an emerging priority of health systems worldwide and central to Sustainable Development Goal 3 (target 3.8). Critical to the achievement of UHC, is quality of care. However, current evidence suggests that quality of care is suboptimal, particularly in low- and middle-income countries. The primary objective of this scoping review was to summarize the existing conceptual and empirical literature on quality of care within the context of UHC and identify knowledge gaps.

Methods

We conducted a scoping review using the Arksey and O’Malley framework and further elaborated by Levac et al. and applied the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews reporting guidelines. We systematically searched MEDLINE, EMBASE, CINAHL-Plus, PAIS Index, ProQuest and PsycINFO for reviews published between 1 January 1995 and 27 September 2021. Reviews were eligible for inclusion if the article had a central focus on UHC and discussed quality of care. We did not apply any country-based restrictions. All screening, data extraction and analyses were completed by two reviewers.

Results

Of the 4128 database results, we included 45 studies that met the eligibility criteria, spanning multiple geographic regions. We synthesized and analysed our findings according to Kruk et al.’s conceptual framework for high-quality systems, including foundations, processes of care and quality impacts. Discussions of governance in relation to quality of care were discussed in a high number of studies. Studies that explored the efficiency of health systems and services were also highly represented in the included reviews. In contrast, we found that limited information was reported on health outcomes in relation to quality of care within the context of UHC. In addition, there was a global lack of evidence on measures of quality of care related to UHC, particularly country-specific measures and measures related to equity.

Conclusion

There is growing evidence on the relationship between quality of care and UHC, especially related to the governance and efficiency of healthcare services and systems. However, several knowledge gaps remain, particularly related to monitoring and evaluation, including of equity. Further research, evaluation and monitoring frameworks are required to strengthen the existing evidence base to improve UHC.
How to improve the dissemination of clinical practice guidelines in the Brazilian Unified Health System? Report of a pilot project
Authors: Pereira Viviane Cássia , Silva Sarah Nascimento , Vidal Ávila Teixeira , Lins Gustavo Veiga e , Barreto Jorge Otávio Maia
Published: March 2023

In Brazil, there have been some initiatives to improve the development of Ministry of Health clinical protocols and therapeutic guidelines (PCDTs in Portuguese, and clinical practice guidelines—CPGs, in English) and their implementation so that best practices can be disseminated and adopted at multiple levels of health systems. One of the initiatives was to conduct a pilot project to improve the format of these CPGs. The objective of this article is to present the processes and results of the pilot project, including the development of a new standardized format for CPGs to promote national dissemination and uptake. The pilot project was designed in three phases: identification and selection of strategies to effectively implement clinical practice guidelines, definition of the ideal characteristics for the format of CPGs, and development and implementation of the new format. Initially, an overview of systematic reviews was conducted to map the global evidence on the effectiveness of dissemination and implementation strategies of CPGs. Among the most effective interventions, a low-cost strategy was selected to improve the format of CPGs, namely a full format and a short format. The two formats were evaluated for usefulness and acceptability by professionals who use or develop CPGs, and after several reiterations, the formats were finalized, considering the progression of care (from diagnosis of the disease to treatment, including specific technologies indicated in each stage of the disease). Related to the technical aspects, the visual presentation of the CPGs was improved, ensuring that key information was easily identified for decision-making by end users. The initial phase of implementation involved 33 clinical conditions, equating to approximately 20% of published CPGs. It is anticipated that disseminating the CPGs in the new formats will promote the accessibility of information and implementation of standardized CPGs by health professionals in the public health sector (servicing more than 210 million Brazilians). Further research should be considered to determine the impact of the use of the new CPGs formats, contributing to the knowledge base related to the implementation of guidelines in Brazil and internationally.
Strengthening health systems and peacebuilding through women’s leadership: a qualitative study
Authors: Meagher Kristen , Khaity Mouna , Hafez Sali , Rodo Mariana , Achi Nassim El , Patel Preeti
Published: March 2023

Background

Active and protracted conflict settings demonstrate the need to prioritise the peace through health agenda. This can be achieved by reorienting attention toward gender diverse leadership and more effective governance within health systems. This approach may enable women to have a greater voice in the decision-making of health and social interventions, thereby enabling the community led and context specific knowledge required to address the root causes of persistent inequalities and inequities in systems and societies.

Methods

We conducted a qualitative study, which included semi-structured interviews with 25 key informants, two focus group discussions and one workshop with humanitarian workers in local and international non-governmental organisations (NGOs), United Nations (UN) agencies, health practitioners, and academics, from Sub-Saharan Africa, Middle East and North Africa (MENA), and Latin America. Findings were then applied to the peacebuilding pyramid designed by John Paul Lederach which provides a practical framework for mediation and conflict resolution in several conflict-affected settings. The purpose of the framework was to propose an adapted conceptualisation of leadership to include women’s leadership in the health system and be more applicable in protracted conflict settings.

Results

Five interrelated themes emerged. First, perceptions of terms such as gender equality, equity, mainstreaming, and leadership varied across participants and contexts. Second, armed conflict is both a barrier and an enabler for advancing women’s leadership in health systems. Third, health systems themselves are critical in advancing the nexus between women’s leadership, health systems and peacebuilding. Fourth, across all contexts we found strong evidence of an instrumental relationship between women’s leadership in health systems in conflict-affected settings and peacebuilding. Lastly, the role of donors emerged as a critical obstacle to advance women’s leadership.

Conclusion

Continuing to empower women against social, cultural, and institutional barriers is crucial, as the emerging correlation between women’s leadership, health systems, and peacebuilding is essential for long-term stability, the right to health, and health system responsiveness.
Effect of focused power ultrasound-mediated perirenal fat modification on primary hypertension: protocol of a multicenter, randomized, double-blinded, sham-controlled study
Authors: Li Menghuan , Shi Jing , Sheng Yanhui , Zhang Yuqing , Wu Tingting , Yang Jiaming , Zhang Kerui , Sun Wei , Kong Xiangqing
Published: March 2023

Background

Perirenal fat plays a key role in sustaining pathological high blood pressure. We aim to investigate the efficacy of intervention for perirenal fat mediated by focused power ultrasound (FPU) on primary hypertension.

Methods

A multicenter, randomized, sham-controlled, double-blinded trial will be implemented in 200 participants with mild to moderate hypertension. All enrolled participants will be randomly allocated to perirenal fat modification (PFM) intervention using FPU or sham-procedure at a ratio of 1:1 and will be followed up at 24 h, 14 days, 30 days, and 90 days after the intervention. The primary endpoint is changes in office systolic blood pressure (SBP) at 30 days compared with baseline. The secondary endpoints include the changes in office SBP from baseline to 90 days, changes in 24-h mean SBP from baseline to 30 days and 90 days, and changes in heart rate from baseline to 30 days. Safety endpoint is defined as any severe adverse events related to the intervention.

Discussion

The present study is the first to use noninvasive FPU to intervene in perirenal fat to achieve the goal of reducing blood pressure for patients with essential hypertension. Our study is expected to provide a new treatment strategy to control high blood pressure.

Trial registration

ClinicalTrials.gov. NCT05049096. Registered on September 7, 2021.

Protocol version: Version 1.3.1, data 23 August 2021.

Sponsor: Prof. Xiangqing Kong is the principal investigator of this trial.
Perirenal fat thickness and liver fat fraction are independent predictors of MetS in adults with overweight and obesity suspected with NAFLD: a retrospective study
Authors: Wang Li , Pan Yuning , Ye Xianwang , Zhu Yongmeng , Lian Yandong , Zhang Hui , Xu Miao , Liu Mengxiao , Ruan Xinzhong
Published: March 2023

Background

Nonalcoholic fatty liver disease (NAFLD) has a multidirectional relationship with metabolic syndrome (MetS) and used to be considered a hepatic manifestation of MetS. Perirenal fat, as a part of visceral adipose tissue (VAT), was reported to be correlated with MetS components, but data for intraorgan fat are lacking. This study was undertaken to assess the value of peripheral and intraorgan fat to predict MetS in adults with overweight and obesity with suspected NAFLD.

Methods

We studied 134 sequential adults (mean age, 31.5 years; 47% female) with overweight and obesity with suspected NAFLD. All participants underwent abdominal magnetic resonance imaging (MRI) examination. Anthropometric and metabolic parameters and perirenal fat thickness (PRFT), subcutaneous adipose tissue thickness (SATT), liver fat fraction (LFF), pancreas fat fraction (PFF), and lumbar spine fat fraction (LSFF) were collected. MetS was defined according to the International Diabetes Federation (IDF) criteria. Statistical analyses included basic statistics, linear correlation and logistic regression analysis.

Results

A total of 63 adults with MetS and 71 adults with advanced liver steatosis (grades 2 and 3) were included in our study. Patients with MetS had greater PRFT (p = 0.026) and LFF (p < 0.001), as well as greater homeostasis model assessment of insulin resistance (HOMA-IR), alanine transaminase (ALT), aspartate transaminase (AST), and decreased SATT. MetS patients had a higher proportion of advanced steatosis than those without MetS (P < 0.001). The MetS score was associated with PRFT and LFF. Logistic regression analysis showed that the PRFT and LFF were independent predictors of MetS after adjusting for age and sex. A cutoff of 9.15 mm for PRFT and 14.68% for LFF could be predictive of MetS.

Conclusions

This study shows that the absolute cutoff level of 9.15 mm for PRFT and 14.68% for LFF may be clinically important markers for identifying patients who are at high risk of MetS among adults with overweight and obesity with suspected NAFLD, irrespective of sex and age. Moreover, ectopic fat levels in pancreas and lumbar spine are positively associated with PRFT.

Trial registration

Not applicable.
Exploring of two different equated instability resistance training programs on measure of physical fitness and lower limb asymmetry in pre-pubertal weightlifters
Authors: Hammami Raouf , Nobari Hadi , Hanen Werfelli , Gene-Morales Javier , Rebai Haithem , Colado Juan C. , Ardigò Luca Paolo
Published: March 2023

Background

Although previous research in pediatric populations has reported performance enhancements following instability resistance training, the effects of different volumes on measures of balance, strength and power and lower limb asymmetry remain unclear.

Objective

To compare the effect of two 8-week instability resistance training programs (IRT1: 2 sets x 8 repetitions, 20% one-repetition maximum (1RM); IRT2: 2 sets x 4 repetitions, 40% 1RM) in balance (center of pressure displacements), 1RM, single-leg jumps, and inter-limb asymmetry of prepubescent weightlifters.

Methods

Thirty-two male athletes (10.94 ± 0.47 yrs, 17.05 ± 0.14 kg/m2, and 6.44 ± 0.93% bodyfat) voluntarily participated and combined IRT (front and back squat, lunge, and deadlift) with their usual weightlifting training. Nonparametric tests evaluated the differences between pre- and post-intervention.

Results

Significant improvements were encountered in all the variables for both groups (effect sizes [ES] from 0.46 to 2.60), except the inter-limb asymmetry and the velocity of displacement of the center of pressure, which did not improve in IRT2. It is also worth highlighting that in the single-leg jumps and center of pressure displacements, whereas no significant differences were observed between IRT1 and IRT2 in the baseline, significant differences appeared in the follow-up measurements.

Conclusion

IRT combined with weight-lifting training improves prepubescent weightlifters’ performance; therefore, strength and conditioning coaches may consider including unstable devices with low loads into an overall conditioning program and warm-ups for prepuberal male weightlifters to promote their physical fitness and potentially decrease inter-limb asymmetry.

Trial registration

This study does not report results related to healthcare interventions using human participants; therefore, it was not prospectively registered.
IL-6/gp130 signaling: a key unlocking regeneration
Authors: Li Ruopu , Li Deqiang , Nie Yu
Published: March 2023

Liver is an organ with notable capacity of regeneration. Reprogramming of hepatocytes towards an immature state is one of the important mechanisms for hepatocyte replenishment. Inflammatory response mediated by IL-6 and its family cytokines has been widely reported closely related with tissue regeneration in myriads of organs. Recently Hui and colleagues reported that the dedifferentiation of hepatocytes depends upon IL-6 signaling from Kupffer cells and the reprogramming of gene expression under the inflammatory condition is different from the regulation of gene expression during embryo hepatocyte specification, highlighting a tight linkage between extracellular microenvironment and parenchymal cell plasticity during tissue regenerative repair.
AAM: a dataset of Artificial Audio Multitracks for diverse music information retrieval tasks
Authors: Ostermann Fabian , Vatolkin Igor , Ebeling Martin
Published: March 2023

We present a new dataset of 3000 artificial music tracks with rich annotations based on real instrument samples and generated by algorithmic composition with respect to music theory. Our collection provides ground truth onset information and has several advantages compared to many available datasets. It can be used to compare and optimize algorithms for various music information retrieval tasks like music segmentation, instrument recognition, source separation, onset detection, key and chord recognition, or tempo estimation. As the audio is perfectly aligned to original MIDIs, all annotations (onsets, pitches, instruments, keys, tempos, chords, beats, and segment boundaries) are absolutely precise. Because of that, specific scenarios can be addressed, for instance, detection of segment boundaries with instrument and key change only, or onset detection only in tracks with drums and slow tempo. This allows for the exhaustive evaluation and identification of individual weak points of algorithms. In contrast to datasets with commercial music, all audio tracks are freely available, allowing for extraction of own audio features. All music pieces are stored as single instrument audio tracks and a mix track, so that different augmentations and DSP effects can be applied to extend training sets and create individual mixes, e.g., for deep neural networks. In three case studies, we show how different algorithms and neural network models can be analyzed and compared for music segmentation, instrument recognition, and onset detection. In future, the dataset can be easily extended under consideration of specific demands to the composition process.
Effect of iron fortification on anaemia and risk of malaria among Ghanaian pre-school children with haemoglobinopathies and different ABO blood groups
Authors: Tchum Samuel Kofi , Sakyi Samuel Asamoah , Arthur Fareed , Adu Bright , Abubakar Latifatu Alhassan , Oppong Felix Boakye , Dzabeng Francis , Amoani Benjamin , Gyan Thomas , Asante Kwaku Poku
Published: March 2023

Background

Haemoglobinopathies such as sickle cell disorder and glucose-6-phosphate dehydrogenase (G6PD) deficiency as well as differences in ABO blood groups have been shown to influence the risk of malaria and/or anaemia in malaria-endemic areas. This study assessed the effect of adding MNP containing iron to home-made weaning meals on anaemia and the risk of malaria in Ghanaian pre-school children with haemoglobinopathies and different ABO blood groups.

Methods

This study was a double-blind, randomly clustered trial conducted within six months among infants and young children aged 6 to 35 months in rural Ghana (775 clusters,n = 860). Participants were randomly selected into clusters to receive daily semiliquid home-prepared meals mixed with either micronutrient powder without iron (noniron group) or with iron (iron group; 12.5 mg of iron daily) for 5 months. Malaria infection was detected by microscopy, blood haemoglobin (Hb) levels were measured with a HemoCue Hb analyzer, the reversed ABO blood grouping microtube assay was performed, and genotyping was performed by PCR–RFLP analysis.

Results

The prevalence of G6PD deficiency among the study participants was 11.2%. However, the prevalence of G6PD deficiency in hemizygous males (8.5%) was significantly higher than that in homozygous females (2.7%) (p = 0.005). The prevalence rates of sickle cell traits (HbAS and HbSC) and sickle cell disorder (HbSS) were 17.5% and 0.5%, respectively. Blood group O was dominant (41.4%), followed by blood group A (29.6%) and blood group B (23.3%), while blood group AB (5.7%) had the least frequency among the study participants. We observed that children on an iron supplement with HbAS had significantly moderate anaemia at the endline (EL) compared to the baseline level (BL) (p = 0.004). However, subjects with HbAS and HbAC and blood groups A and O in the iron group had a significantly increased number of malaria episodes at EL than at BL (p < 0.05). Furthermore, children in the iron group with HbSS (p < 0.001) and the noniron group with HbCC (p = 0.010) were significantly less likely to develop malaria.

Conclusions

Iron supplementation increased anaemia in children with HbAS genotypes and provided less protection against malaria in children with HbAC and AS and blood groups A and O.

Trial registration

clinicaltrials.gov Identifier:NCT01001871. Registered 27/10/2009.

Registration number:https://clinicaltrials.gov/ct2/show/record/NCT01001871.
Local design and manufacturing of patient-specific implant using Anatomage Medical Design Studio software: proof of concept - Botswana’s 1st case report
Authors: Nkhwa Shathani , Montshiwa Thapelo , de Beer Deon , Booysen Gerrie , van den Heever Cules , Els Johan , Heydenrych Andre , Kebaetse Maikutlo
Published: March 2023

Background

Botswana, like most sub-Sahara African nations, uses conventional orthopaedic implants that are sourced from major manufactures in the West. The implants are mass-produced and designed with universal configurations to fit an average patient. During surgery, surgeons thus sometimes bend the implants to match the individual bone anatomy, especially for paediatric patients and those with unique deformities, thus risking implant failure. The purpose of this project was to show the feasibility of developing safe and effective patient-specific orthopaedic implants in a low-resourced market.

Methods

CT Scan slice files of a paediatric patient with Ollier’s disease were used to reconstruct the lower limb anatomy. The resultant files were 3D printed into prototypes that showed severe right knee valgus deformity. The surgeon used the prototype to plan for corrective femoral osteotomy and the required implant. The implant design and planned surgery were subsequently simulated on the Medical Design Studio software for proper fitting before final implant printing. Surgery was then performed, followed by 12 weeks of physiotherapy.

Results

Post-surgical x-rays demonstrated good implant positioning and knee joint alignment. At 18 months of post-surgical follow-up, the child was pain-free, could perform full squats, and ambulation was near-normal, without the use of an assistive device.

Conclusions

It is feasible to develop effective, patient-specific implants for selected orthopaedic cases in a low-resourced country. This work could improve surgical and rehabilitation outcomes for selected paediatric patients and those with severe bone deformities.
Scientist Spotlights in Secondary Schools: Student Shifts in Multiple Measures Related to Science Identity after Receiving Written Assignments
Authors: Ovid Dax , Abrams L’vannah , Carlson Tess , Dieter Mark , Flores Paulos , Frischer David , Goolish Jolie , Bernt Michelle La-Fevre , Lancaster Amber , Lipski Christopher , Luna Joshua Vargas , Luong Lucy M. C. , Mullin Marlene , Newman Mia Janelle , Quintero Carolina , Reis Julie , Robinson Freja , Ross Allison James , Simon Hilary , Souza Gianne , Taylor Jess , Ward Katherine E. , White Yvonne Lever , Witkop Emily , Yang Christine , Zenilman Aliza , Zhang Eddie , Schinske Jeffrey N. , Tanner Kimberly D.
Published: March 2023

Secondary student outcomes after completing at least three Scientist Spotlight assignments were investigated through multi-school collaborations. Across demographics, students significantly increased relatability to and nonstereotypes about scientists. Larger pre–post shifts in students’ relatability to scientists correspond to in-class discussions.
Polygenic Pharmacogenomic Markers as Predictors of Toxicity Phenotypes in the Treatment of Acute Lymphoblastic Leukemia: A Single-Center Study
Authors: Larkin Trisha , Kashif Reema , Elsayed Abdelrahman H. , Greer Beate , Mangrola Karna , Rafiee Roya , Nguyen Nam , Shastri Vivek , Horn Biljana , Lamba Jatinder K.
Published: March 2023

PURPOSE

Acute lymphoblastic leukemia (ALL) is the most prevalent cause of childhood cancer and requires a long course of therapy consisting of three primary phases with interval intensification blocks. Although these phases are necessary to achieve remission, the primary chemotherapeutic agents have potentially serious toxicities, which may lead to delays or discontinuations of therapy. The purpose of this study was to perform a comprehensive pharmacogenomic evaluation of common antileukemic agents and develop a polygenic toxicity risk score predictive of the most common toxicities observed during ALL treatment.

METHODS

This cross-sectional study included 75 patients with pediatric ALL treated between 2012 and 2020 at the University of Florida. Toxicity data were collected within 100 days of initiation of therapy using CTCAE v4.0 for toxicity grading. For pharmacogenomic evaluation, single-nucleotide polymorphisms (SNPs) and genes were selected from previous reports or PharmGKB database. 116 unique SNPs were evaluated for incidence of various toxicities. A multivariable multi-SNP modeling for up to 3-SNP combination was performed to develop a polygenic toxicity risk score of prognostic value.

RESULTS

We identified several SNPs predictive of toxicity phenotypes in univariate analysis. Further multivariable SNP-SNP combination analysis suggest that susceptibility to chemotherapy-induced toxicities is likely multigenic in nature. For 3-SNPscore models, patients with high scores experienced increased risk of GI ( P = 2.07E-05, 3 SNPs: TYMS-rs151264360/FPGS-rs1544105/GSTM1-GSTM5-rs3754446), neurologic ( P = .0005, 3 SNPs: DCTD-rs6829021/SLC28A3-rs17343066/CTPS1-rs12067645), endocrine ( P = 4.77E-08, 3 SNPs: AKR1C3-rs1937840/TYMS-rs2853539/CTH-rs648743), and heme toxicities ( P = .053, 3 SNPs: CYP3A5-rs776746/ABCB1-rs4148737/CTPS1-rs12067645).

CONCLUSION

Our results imply that instead of a single-SNP approach, SNP-SNP combinations in multiple genes in drug pathways increases the robustness of prediction of toxicity. These results further provide promising SNP models that can help establish clinically relevant biomarkers allowing for greater individualization of cancer therapy to maximize efficacy and minimize toxicity for each patient.
The Transmembrane Protein TM4SF3 Interacts With AR and AR-V7 and is Recruited to AR Target Genes
Authors: Khatiwada Prabesh , Rimal Ujjwal , Han Zhengyang , Malla Mamata , Zhou Jun , Shemshedini Lirim
Published: March 2023

Prostate cancer transitions from an early treatable form to the lethal castration-resistant prostate cancer (CRPC). Androgen receptor (AR) and constitutively active AR splice variants, such as AR-V7, may be major drivers of CRPC. Our laboratory recently identified a novel mechanism of AR regulation via the transmembrane protein transmembrane 4 superfamily 3 (TM4SF3), which exhibits a physical interaction, nuclear colocalization, and mutual stabilization with AR. Here, we have mapped the interaction domains within AR and TM4SF3 and discovered that TM4SF3 also physically interacts with AR-V7, regulating its protein stability and the viability of CRPC cells expressing AR-V7. Ubiquitination of TM4SF3 and AR-V7 was detected for the first time and TM4SF3 interaction with either AR or AR-V7 resulted in mutual deubiquitination of both proteins, showing that mutual stabilization results from deubiquitination. Interestingly, nuclear TM4SF3 was co-recruited to the promoters of AR- and AR-V7-regulated genes and required for their expression, showing that TM4SF3 interaction is critical for their transcriptional functions. The results collectively show the multiple critical regulatory functions of TM4SF3 on AR or AR-V7 in prostate cancer cells.
Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency
Authors: Keatinge Marcus , Gegg Matthew E. , Watson Lisa , Mortiboys Heather , Li Nan , Dunning Mark , Ailani Deepak , Bui Hai , van Rens Astrid , Lefeber Dirk J. , Schapira Anthony H. V. , MacDonald Ryan B. , Bandmann Oliver
Published: March 2023

Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants of SMPD1 are also overrepresented in PD cohorts, whereas a reduction of its encoded enzyme (acid sphingomyelinase or ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how the combined deficiencies of both enzymes might interact to modulate PD has yet to be explored. Therefore, we created a double-knockout (DKO) zebrafish line for both gba1 (or gba) and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO line compared to those for single mutants. Unexpectedly, DKO zebrafish maintained conventional swimming behaviour and had normalised neuronal gene expression signatures compared to those of single mutants. We further identified rescue of mitochondrial Complexes I and IV in DKO zebrafish. Despite having an unexpected rescue effect, our results confirm ASM as a modifier of GBA1 deficiency in vivo. Our study highlights the need for validating how genetic variants and enzymatic deficiencies may interact in vivo.
Feasibility and Safety of Tailored Lymphadenectomy Using Sentinel Node-Navigated Surgery in Patients with High-Risk T1 Esophageal Adenocarcinoma
Authors: Frederiks Charlotte N. , Overwater Anouk , Bergman Jacques J. G. H. M. , Pouw Roos E. , de Keizer Bart , Bennink Roel J. , Brosens Lodewijk A. A. , Meijer Sybren L. , van Hillegersberg Richard , van Berge Henegouwen Mark I. , Ruurda Jelle P. , Gisbertz Suzanne S. , Weusten Bas L. A. M.
Published: March 2023

Background

Selective lymphadenectomy using sentinel node-navigated surgery (SNNS) might offer a less invasive alternative to esophagectomy in patients with high-risk T1 esophageal adenocarcinoma (EAC). The aim of this study was to evaluate the feasibility and safety of a new treatment strategy, consisting of radical endoscopic resection of the tumor followed by SNNS.

Methods

In this multicenter pilot study, ten patients with a radically resected high-risk pT1cN0 EAC underwent SNNS. A hybrid tracer of technetium-99m nanocolloid and indocyanine green was injected endoscopically around the resection scar the day before surgery, followed by preoperative imaging. During surgery, sentinel nodes (SNs) were identified using a thoracolaparoscopic gammaprobe and fluorescence-based detection, and subsequently resected. Endpoints were surgical morbidity and number of detected and resected (tumor-positive) SNs.

Results

Localization and dissection of SNs was feasible in all ten patients (median 3 SNs per patient, range 1–6). The concordance between preoperative imaging and intraoperative detection was high. In one patient (10%), dissection was considered incomplete after two SNs were not identified intraoperatively. Additional peritumoral SNs were resected in four patients (40%) after fluorescence-based detection. In two patients (20%), a (micro)metastasis was found in one of the resected SNs. One patient experienced neuropathic thoracic pain related to surgery, while none of the patients developed functional gastroesophageal disorders.

Conclusions

SNNS appears to be a feasible and safe instrument to tailor lymphadenectomy in patients with high-risk T1 EAC. Future research with long-term follow-up is warranted to determine whether this esophageal preserving strategy is justified for high-risk T1 EAC.
Creating connections: developing an online space for cross-regional mentorship and network building in the dementia research field
Authors: Fullerton Josie , Bettencourt Conceicao , Daniels Michael , Mclean Fiona , Simpson Susan , Smith Adam , Woodling Nathan , Kerr Fiona
Published: March 2023

Background

Effective development and retention of talented early-career researchers (ECRs) is essential to the continued success of biomedical science research fields. To this end, formal mentorship programmes (where researchers are paired with one or more mentors beyond their direct manager) have proven to be successful in providing support and expanding career development opportunities. However, many programmes are limited to pools of mentors and mentees within one institute or geographical area, highlighting that cross-regional connections may be a missed opportunity in many mentorship schemes.

Methods

Here, we aimed to address this limitation through our pilot cross-regional mentorship scheme, creating reciprocal mentor-mentee pairings between two pre-established networks of Alzheimer’s Research UK (ARUK) Network-associated researchers. We carefully created 21 mentor-mentee pairings between the Scotland and University College London (UCL) networks in 2021, with surveys conducted to assess mentor/mentee satisfaction with the programme.

Results

Participants reported very high satisfaction with the nature of the pairings and the mentors’ contribution to the career development of mentees; a majority also reported that the mentorship scheme increased their connections outside of their home network. Our assessment of this pilot programme is that it supports the utility of cross-regional mentorship schemes for ECR development. At the same time, we highlight the limitations of our programme and recommend areas for improvement in future programmes, including greater consideration of support for minoritized groups and the need for additional training for mentors.

Conclusions

In conclusion, our pilot scheme generated successful and novel mentor-mentee pairings across pre-existing networks; both of which reported high satisfaction with pairings, ECR career and personal development, and the formation of new cross-network connections. This pilot may serve as a model for other networks of biomedical researchers, where existing networks within medical research charities can act as a scaffold to build new cross-regional career development opportunities for researchers.
Methodological Approaches to the Formation of Cognitive Universal Educational Activities in Younger Schoolchildren
Authors: Ukropova A.
Published: March 2023

The article highlights the methods of working with primary schoolchildren, which contribute to the formation of their cognitive universal educational activities. The mastery of a set of universal educational activities by younger schoolchildren, in turn, is considered in the Federal State Educational Standard for Primary General Education as the most important requirement - the formation of meta-subject learning outcomes. The article provides interesting examples of tasks offered to students in the lessons of the world around them, which ensure the development of their basic logical operations, initial research activities, the ability to work with information presented in various forms, as well as modeling and design skills.
Retail Sample Boxes: Counteracting the Adverse Effect of Accelerated Learning via Future Credit
Authors: Yazdani Alireza , Çil Eren B. , Pangburn Michael
Published: March 2023

Problem definition: Consumers often try a few varieties of an experience product before establishing a shopping routine. In retailing, a sample box typically refers to a package of multiple trial-sized varieties within a product category. Sample boxes potentially create value by helping consumers resolve their uncertainties regarding these varieties earlier and at a lower cost. In this paper, we study how firms and consumers share this added value under different market scenarios. We also derive the optimal pricing of sample boxes in product categories for which consumers make ongoing purchases over time. Academic/practical relevance: We thus extend the literature by proposing a framework that integrates sequential search and seller-induced learning. Methodology: We analyze a firm’s pricing decisions when consumers either purchase full-sized options sequentially or bypass that process via a sample box. We use dynamic programming to analyze consumers’ search problem (in the absence of a sample box) and nonlinear optimization to analyze the firm’s problem. Results: As anticipated, the informational value of a sample box yields an optimal price premium relative to the prices of individual products. Despite this price premium, we show that the firm’s expected profit may decrease because a sample box accelerates consumer learning, and thus, it may help consumers settle upon an outside option earlier. We establish that a firm can reverse the potential adverse profit impact of selling sample boxes by introducing an optimally specified future credit. Managerial implications: Offering sample boxes is a common practice in retailing. Contrasting the resulting expected profits with and without the sample box option, our results highlight that managers may be ill-advised to offer a sample box in the absence of the future credit mechanism. This study is the first to address the pricing of sample boxes and show the optimality of offering credit toward a subsequent purchase.

Supplemental Material: The online appendix is available at https://doi.org/10.1287/msom.2023.1206 .
Humanitarian Relief Distribution Problem: An Adjustable Robust Optimization Approach
Authors: Avishan Farzad , Elyasi Milad , Yanıkoğlu İhsan , Ekici Ali , Özener O. Örsan
Published: March 2023

Management of humanitarian logistics operations is one of the most critical planning problems to be addressed immediately after a disaster. The response phase covers the first 12 hours after the disaster and is prone to uncertainties because of debris and gridlock traffic influencing the dispatching operations of relief logistics teams in the areas affected. Moreover, the teams have limited time and resources, and they must provide equitable distribution of supplies to affected people. This paper proposes an adjustable robust optimization approach for the associated humanitarian logistics problem. The approach creates routes for relief logistics teams and decides the service times of the visited sites to distribute relief supplies by taking the uncertainty in travel times into account. The associated model allows relief logistics teams to adjust their service decisions according to the revealed information during the process. Hence, our solutions are robust for the worst-case realization of travel times, but still more flexible and less conservative than those of static robust optimization. We propose novel reformulation techniques to model these adjustable decisions. The resulting models are computationally challenging optimization problems to be solved by exact methods, and, hence, we propose heuristic algorithms. The state-of-the-art heuristic, which is based on clustering and a dedicated decision-rule algorithm, yields near-optimal results for medium-sized instances and is scalable even for large-sized instances. We have also shown the effectiveness of our approach in a case study using a data set obtained from an earthquake that hit the Van province of Turkey in 2011.

History: This paper has been accepted for the Transportation Science Special Issue on Emerging Topics in Transportation Science and Logistics.

Supplemental Material: The online appendix is available at https://doi.org/10.1287/trsc.2023.1204 .
How to become a compassionate leader
Authors: Foster Sam
Published: March 2023

Sam Foster, Chief Nurse, Oxford University Hospitals, discusses a set of attributes that will enable managers to create workplace environments within which colleagues are empathetic and supportive of one another
Beclometasone inhaler-induced recovery of refractory peri-ileostomy skin complications
Authors: McDonald Mary , Connelly Tara M , Brett Aishling , McCullough Peter , Cooke Fiachra , Neary Peter
Published: March 2023

Peristomal skin complications (PSCs) are relatively common in ostomy patients, particularly in those with ileostomies. Non-healing irritation presents a clinical challenge and leads to pain and impaired quality of life for patients. Methods: The cases of four ileostomy patients experiencing severe, challenging PSCs refractory to appliance changes, conventional dressings and barrier creams are discussed. Findings: The cases of one male and one female patient with an end ileostomy post-subtotal colectomy for ulcerative colitis, one female with a defunctioning ileostomy post-anterior resection for sigmoid carcinoma and one male with an end ileostomy with a complex Crohn's surgical history are described. Two puffs of a 250 mcg metered dose beclometasone inhaler were applied to the affected skin once or twice daily. Treatment ranged from 6 to 21 days. Complete resolution was seen in all cases. Conclusion: Topical use of a beclometasone inhaler was effective for severe peri-ileostomy PSC secondary to four different aetiologies. Further studies are warranted to determine the effectiveness of this treatment in a larger patient cohort.