bluuebunny/crossref_metadata_2025 huggingface dataset:
Racial disparities in breast cancer preclinical and clinical models
Authors: Clarke Shannique , Chin Sheray N. , Dodds Leah , George Sophia H. L. , Badal Simone
Published: August 2022

Breast cancer (BCa) has long been a health burden to women across the globe. However, the burden is not equally carried across races. Though the manifestation and behavior of BCa differs among racial groups, the racial representation of models used in preclinical trials and clinical trial participants lacks this heterogeneity. Women of African Ancestry (WAA) are disproportionately afflicted by having an increased risk of developing BCas that are more aggressive in nature, and consequently suffer from poorer outcomes relative to women of European ancestry (WEA). Notwithstanding this, one of the most commonly used tools in studying BCa, cell lines, exhibit a sizeable gap in cell line derivatives of WEA relative to WAA. In this review, we summarize the available BCa cell lines grouped by race by major suppliers, American Type Culture Collection (ATCC) and the European Collection of Authenticated Cell Cultures (ECACC). Next, examined the enrollment of WAA in clinical trials for BCa. Of the cell lines found provided by ATCC and ECACC, those derived from WEA constituted approximately 80% and 94%, respectively. The disparity is mirrored in clinical trial enrollment where, on average, WEA made up more than 70% of participants in trials found where ancestry information was provided. As both experimental models and clinical trial participants primarily consist of WEA, results may have poorer translatability toward other races. This highlights the need for greater racial diversity at the preclinical and clinical levels to more accurately represent the population and strengthen the translatability of results.
Discovery and validation of dominantly inherited Alzheimer’s disease mutations in populations from Latin America
Authors: Takada Leonel Tadao , Aláez-Verson Carmen , Burgute Bhagyashri D. , Nitrini Ricardo , Sosa Ana Luisa , Castilhos Raphael Machado , Chaves Marcia Fagundes , Longoria Erika-Mariana , Carrillo-Sánchez Karol , Brucki Sonia Maria Dozzi , Flores-Lagunes Luis Leonardo , Molina Carolina , Olivares Marcos Jimenez , Ziegemeier Ellen , Petranek Jennifer , Goate Alison M. , Cruchaga Carlos , Renton Alan E. , Fernández Maria Victoria , Day Gregory S. , McDade Eric , Bateman Randall J. , Karch Celeste M. , Llibre-Guerra Jorge J. ,   for the Dominantly Inherited Alzheimer Network
Published: August 2022

Background

In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations.

Methods

Clinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios.

Results

We identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36–54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce Aβ profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation.

Conclusions

Our study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD.
Development of multivariable prediction models for institutionalization and mortality in the full spectrum of Alzheimer’s disease
Authors: Mank Arenda , van Maurik Ingrid S. , Rijnhart Judith J. M. , bakker Els D. , Bouteloup Vincent , Le Scouarnec Lisa , Teunissen Charlotte E. , Barkhof Frederik , Scheltens Philip , Berkhof Johannes , van der Flier Wiesje M.
Published: August 2022

Background

Patients and caregivers express a desire for accurate prognostic information about time to institutionalization and mortality. Previous studies predicting institutionalization and mortality focused on the dementia stage. However, Alzheimer’s disease (AD) is characterized by a long pre-dementia stage. Therefore, we developed prediction models to predict institutionalization and mortality along the AD continuum of cognitively normal to dementia.

Methods

This study included SCD/MCI patients (subjective cognitive decline (SCD) or mild cognitive impairment (MCI)) and patients with AD dementia from the Amsterdam Dementia Cohort. We developed internally and externally validated prediction models with biomarkers and without biomarkers, stratified by dementia status. Determinants were selected using backward selection (p<0.10). All models included age and sex. Discriminative performance of the models was assessed with Harrell’s C statistics.

Results

We included n=1418 SCD/MCI patients (n=123 died, n=74 were institutionalized) and n=1179 patients with AD dementia (n=413 died, n=453 were institutionalized). For both SCD/MCI and dementia stages, the models for institutionalization and mortality included after backward selection clinical characteristics, imaging, and cerebrospinal fluid (CSF) biomarkers. In SCD/MCI, the Harrell’s C-statistics of the models were 0.81 (model without biomarkers: 0.76) for institutionalization and 0.79 (model without biomarker: 0.76) for mortality. In AD-dementia, the Harrell’s C-statistics of the models were 0.68 (model without biomarkers: 0.67) for institutionalization and 0.65 (model without biomarker: 0.65) for mortality. Models based on data from amyloid-positive patients only had similar discrimination.

Conclusions

We constructed prediction models to predict institutionalization and mortality with good accuracy for SCD/MCI patients and moderate accuracy for patients with AD dementia. The developed prediction models can be used to provide patients and their caregivers with prognostic information on time to institutionalization and mortality along the cognitive continuum of AD.
Endogenous Follistatin-like 1 guarantees the immunomodulatory properties of mesenchymal stem cells during liver fibrotic therapy
Authors: Zheng Xiaohong , Zhou Xia , Ma Gang , Yu Jiahao , Zhang Miao , Yang Chunmei , Hu Yinan , Ma Shuoyi , Han Zheyi , Ning Wen , Jin Boquan , Zhou Xinmin , Wang Jingbo , Han Ying
Published: August 2022

Background

Mesenchymal stem cell (MSC) therapy has been shown to be a promising option for liver fibrosis treatment. However, critical factors affecting the efficacy of MSC therapy for liver fibrosis remain unknown. Follistatin-like 1 (FSTL1), a TGF-β-induced matricellular protein, is documented as an intrinsic regulator of proliferation and differentiation in MSCs. In the present study, we characterized the potential role of FSTL1 in MSC-based anti-fibrotic therapy and further elucidated the mechanisms underlying its action.

Methods

Human umbilical cord-derived MSCs were characterized by flow cytometry. FSTL1low MSCs were achieved by FSTL1 siRNA. Migration capacity was evaluated by wound-healing and transwell assay. A murine liver fibrotic model was created by carbon tetrachloride (CCl4) injection, while control MSCs or FSTL1low MSC were transplanted via intravenous injection 12 weeks post CCl4 injection. Histopathology, liver function, fibrosis degree, and inflammation were analysed thereafter. Inflammatory cell infiltration was evaluated by flow cytometry after hepatic nonparenchymal cell isolation. An MSC-macrophage co-culture system was constructed to further confirm the role of FSTL1 in the immunosuppressive capacity of MSCs. RNA sequencing was used to screen target genes of FSTL1.

Results

FSTL1low MSCs had comparable gene expression for surface markers to wildtype but limited differentiation and migration capacity. FSTL1low MSCs failed to alleviate CCl4-induced hepatic fibrosis in a mouse model. Our data indicated that FSTL1 is essential for the immunosuppressive action of MSCs on inflammatory macrophages during liver fibrotic therapy. FSTL1 silencing attenuated this capacity by inhibiting the downstream JAK/STAT1/IDO pathway.

Conclusions

Our data suggest that FSTL1 facilitates the immunosuppression of MSCs on macrophages and that guarantee the anti-fibrotic effect of MSCs in liver fibrosis.
Effects of smoking on the tissue regeneration-associated functions of human endometrial stem cells via a novel target gene SERPINB2
Authors: Park Se-Ra , Kim Seong-Kwan , Kim Soo-Rim , Yu Wook-Joon , Lee Seung-Jin , Lee Hwa-Yong
Published: August 2022

Background

Smokers directly inhale mainstream cigarette smoke, which contains numerous known and potential toxic substances, and thus, smoking is expected to have broad harmful effects that cause tissue injury and dysfunction. Interestingly, many studies have suggested that the recent decline in female fertility and increased rate of spontaneous abortion could be associated with increased smoking rates. Indeed, women that smoked for 10 years or more were reported to have a ~ 20% higher infertility rate than women that had never smoked. However, the reasons for the underlying harmful aspects of smoking on female fertility remain a matter of debate. Importantly, a previous study revealed that resident endometrial stem cell deficiency significantly limits the cyclic regeneration potential of endometrium, which, in turn, decreases successful pregnancy outcomes. In this context, we postulated that exposure to mainstream cigarette smoke extracts might decrease female fertility by inhibiting the functions of resident endometrial stem cells.

Methods

We investigated whether cigarette mainstream smoke exposure directly inhibits various tissue regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, pluripotency, and differentiation capacity in vitro. Next, we determined whether SERPINB2 mediates cigarette smoke-induced suppressive effects on various tissue regeneration-associated functions by depleting SERPINB2 expression with specific shRNA targeting SERPINB2. Mice were injected intraperitoneally with low (0.5 mg/kg) or high (1 mg/kg) doses of cigarette smoke extract (10 times for two weeks), and endometrial stem cells were then isolated from mice uterine tissues.

Results

We found that exposure to cigarette smoke extracts remarkably suppressed various tissue regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, multilineage differentiation ability, and pluripotency in vitro and in vivo by activating the SERPINB2 gene. Indeed, cigarette smoke-induced inhibitory effects on various endometrial stem cell functions were significantly abolished by SERPINB2 knockdown.

Conclusions

These findings provide valuable information on the harmful effects of cigarette smoking on resident endometrial stem cells and hopefully will facilitate the developments of promising therapeutic strategies for subfertile or infertile women that smoke cigarettes.
Biframes and some of their properties
Authors: Firouzi Parizi Maryam , Alijani Azadeh , Dehghan Mohammad Ali
Published: August 2022

Recently, frame multipliers, pair frames, and controlled frames have been investigated to improve the numerical efficiency of iterative algorithms for inverting the frame operator and other applications of frames. In this paper, the concept of biframe is introduced for a Hilbert space. A biframe is a pair of sequences in a Hilbert space that applies to an inequality similar to a frame inequality. Also, it can be regarded as a generalization of controlled frames and a special kind of pair frames. The basic properties of biframes are investigated based on the biframe operator. Then, biframes are classified based on the type of their constituent sequences. In particular, biframes for which one of the constituent sequences is an orthonormal basis

$\{e_{k}\}_{k=1}^{\infty}$

{

e
k

}

k
=
1

∞

are studied. Then, a new class of Riesz bases denoted by

$[\{e_{k}\}]$

[
{

e
k

}
]

is introduced and is called b-Riesz bases. An interesting result is also proved, showing that the set of all b-Riesz bases is a proper subset of the set of all Riesz bases. More precisely, b-Riesz bases induce an equivalence relation on

$[\{e_{k}\}]$

[
{

e
k

}
]

.
Determining total energy expenditure in 3–6-year-old Japanese pre-school children using the doubly labeled water method
Authors: Teramoto Keisuke , Otoki Kodo , Muramatsu Erina , Oya Chika , Kataoka Yui , Igawa Shoji
Published: August 2022

The doubly labeled water (DLW, 2H218O) method for calculating the total production of CO2 over several days is currently considered to be the most accurate technique for the measurement of total energy expenditure (TEE), and the results obtained using this method have been used to review energy requirements. Presently, there is limited data available on TEE in Japanese children. The objective of this study was to assess the TEE in pre-school Japanese children using the DLW method. We used a cross-sectional population of 140 children (69 boys and 71 girls) aged 3–6 years. TEE was measured using the DLW method over 8 days under free-living conditions. The average weights (kg) of the boys and girls were 15.6 ± 2.5 and 15.0 ± 2.1 for the 3–4 years old and 19.8 ± 3.8 and 19.6 ± 2.7 for the 5–6 years old, respectively. The corresponding TEE (kcal/day) was 1260.9 ± 357.8 and 1265.2 ± 408.0, and 1682.3 ± 489.0 and 1693.1 ± 473.3, respectively, showing a significant difference with respect to age. Furthermore, TEE per body weight (kcal/kg/day) was 83.2 ± 29.2 and 84.9 ± 26.6, and 85.4 ± 23.2 and 86.7 ± 22.6, respectively. However, when TEE was adjusted for body weight or fat-free mass, there were no age or sex differences. We conclude that in Japanese children, TEE in those aged 3–4 years was similar to the current Ministry of Health recommendations. However, TEE in children aged 5–6 years was slightly higher than the recommendations. Based on these findings, the present results obtained from a large number of participants will provide valuable reference data for Japanese children.
Microbial risk score for capturing microbial characteristics, integrating multi-omics data, and predicting disease risk
Authors: Wang Chan , Segal Leopoldo N. , Hu Jiyuan , Zhou Boyan , Hayes Richard B. , Ahn Jiyoung , Li Huilin
Published: August 2022

Background

With the rapid accumulation of microbiome-wide association studies, a great amount of microbiome data are available to study the microbiome’s role in human disease and advance the microbiome’s potential use for disease prediction. However, the unique features of microbiome data hinder its utility for disease prediction.

Methods

Motivated from the polygenic risk score framework, we propose a microbial risk score (MRS) framework to aggregate the complicated microbial profile into a summarized risk score that can be used to measure and predict disease susceptibility. Specifically, the MRS algorithm involves two steps: (1) identifying a sub-community consisting of the signature microbial taxa associated with disease and (2) integrating the identified microbial taxa into a continuous score. The first step is carried out using the existing sophisticated microbial association tests and pruning and thresholding method in the discovery samples. The second step constructs a community-based MRS by calculating alpha diversity on the identified sub-community in the validation samples. Moreover, we propose a multi-omics data integration method by jointly modeling the proposed MRS and other risk scores constructed from other omics data in disease prediction.

Results

Through three comprehensive real-data analyses using the NYU Langone Health COVID-19 cohort, the gut microbiome health index (GMHI) multi-study cohort, and a large type 1 diabetes cohort separately, we exhibit and evaluate the utility of the proposed MRS framework for disease prediction and multi-omics data integration. In addition, the disease-specific MRSs for colorectal adenoma, colorectal cancer, Crohn’s disease, and rheumatoid arthritis based on the relative abundances of 5, 6, 12, and 6 microbial taxa, respectively, are created and validated using the GMHI multi-study cohort. Especially, Crohn’s disease MRS achieves AUCs of 0.88 (0.85–0.91) and 0.86 (0.78–0.95) in the discovery and validation cohorts, respectively.

Conclusions

The proposed MRS framework sheds light on the utility of the microbiome data for disease prediction and multi-omics integration and provides a great potential in understanding the microbiome’s role in disease diagnosis and prognosis.
Local tips, global impact: community-driven measures as avenues of promoting inclusion in the control of neglected tropical diseases: a case study in Kenya
Authors: Ochola Elizabeth A. , Karanja Diana M. S. , Elliott Susan J.
Published: August 2022

Background

Neglected tropical diseases (NTDs) affect poor populations with little or no ‘political voice’ to influence control activities. While most NTDs have interventions that work, the biggest challenge remains in delivering targeted interventions to affected populations residing in areas experiencing weak health systems. Despite the upward development trends in most countries of sub-Saharan Africa (SSA), the healthcare worker to population ratio remains exceptionally low, with some areas not served at all; thus, there is a need to involve other personnel for school and community-based healthcare approaches. Nonetheless, the current community-based programs suffer from inconsistent community participation due to a lack of coordinated response, and an expanded intervention agenda that lacks context-specific solutions applicable to rural, urban, and marginalized areas.

Methods

This research investigated the capacity of local communities to address the burden of NTDs. Informed by the social theory of human capability, the research collected primary qualitative data by conducting key informant interviews and focus group discussions of people infected or affected by NTDs. The interview data were collected and transcribed verbatim for thematic analysis using Nvivo version 12.

Results

Our findings reveal, first, a need for intersectoral collaboration between governments and affected populations for inclusive and sustainable NTD solutions. Second, a ‘bottom-up’ approach that enhances capacity building, sensitization, and behaviour change for improved uptake of NTD interventions. Third, the enforcement of Public Health Legislative Acts that mandates the reporting and treatment of NTDs such as leprosy. Fourth, the establishment of support groups and counseling services to assist persons suffering from debilitating and permanent effects of NTDs.

Conclusions

Our research demonstrates the importance of human agency in encouraging new forms of participation leading to the co-production of inclusive and sustainable solutions against NTDs.
Solar spectral management for natural photosynthesis: from photonics designs to potential applications
Authors: Shen Lihua , Yin Xiaobo
Published: August 2022

Photosynthesis is the most important biological process on Earth that converts solar energy to chemical energy (biomass) using sunlight as the sole energy source. The yield of photosynthesis is highly sensitive to the intensity and spectral components of light received by the photosynthetic organisms. Therefore, photon engineering has the potential to increase photosynthesis. Spectral conversion materials have been proposed for solar spectral management and widely investigated for photosynthesis by modifying the quality of light reaching the organisms since the 1990s. Such spectral conversion materials manage the photon spectrum of light by a photoconversion process, and a primary challenge faced by these materials is increasing their efficiencies. This review focuses on emerging spectral conversion materials for augmenting the photosynthesis of plants and microalgae, with a special emphasis on their fundamental design and potential applications in both greenhouse settings and microalgae cultivation systems. Finally, a discussion about the future perspectives in this field is made to overcome the remaining challenges.
Signet-ring cell carcinoma of the appendix with ganglioneuromatosis: a case report
Authors: Sato Ayami , Sato Yu , Hiruta Nobuyuki , Oshiro Takashi , Yoshida Yutaka , Urita Tasuku , Kitahara Tomoaki , Kadoya Kengo , Nabekura Taiki , Moriyama Yuki , Okazumi Shinichi
Published: August 2022

Background

Primary cancer of the appendix, especially signet-ring cell carcinoma, is an uncommon disease, and it is rarely suspected before surgery. Diffuse intestinal ganglioneuromatosis that is not associated with neurofibromatosis-1 or multiple endocrine neoplasia 2b is also rare. The most frequent symptoms caused by it are changes in bowel habits, abdominal pain, and occlusive episodes.

Case presentation

The patient was a 48-year-old woman who had a month-long history of chronic abdominal pain, fullness, constipation, and diarrhoea. Enhanced computed tomography showed a 100-mm irregular swelling in the appendix and thickening of the appendiceal wall with cystic dilatation. Based on a preoperative diagnosis of appendiceal cancer, the patient underwent laparoscopic ileocecal resection with D3 lymph node dissection. Pathological diagnosis revealed a signet-ring cell carcinoma of the appendix with ganglioneuromatosis. The patient completed four courses of capecitabine plus oxaliplatin (CAPEOX) as postoperative adjuvant chemotherapy, and 23-month postoperative outcome was noneventful without recurrence.

Conclusion

We report a signet-ring cell carcinoma of the appendix that was detected early because of its presence with ganglioneuromatosis.
Feasibility of the Transport PLUS intervention to improve the transitions of care for patients transported home by ambulance: a non-randomized pilot study
Authors: Munjal Kevin G. , Yeturu Sai Kaushik , Chapin Hugh H. , Tan Nadir , Gregoriou Diana , Garcia Daniela , Grudzen Corita , Hwang Ula , Morano Barbara , Neher Hayley , Gorbenko Ksenia , Youngblood Glen , Misra Anjali , Dietrich Staley , Gonzalez Cyndi , Appel Giselle , Jacobs Erica , Siu Albert , Richardson Lynne D.
Published: August 2022

Background

The growing population of patients over the age of 65 faces particular vulnerability following discharge after hospitalization or an emergency room visit. Specific areas of concern include a high risk for falls and poor comprehension of discharge instructions. Emergency medical technicians (EMTs), who frequently transport these patients home from the hospital, are uniquely positioned to aid in mitigating transition of care risks and are both trained and utilized to do so using the Transport PLUS intervention.

Methods

Existing literature and focus groups of various stakeholders were utilized to develop two checklists: the fall safety assessment (FSA) and the discharge comprehension assessment (DCA). EMTs were trained to administer the intervention to eligible patients in the geriatric population. Using data from the checklists, follow-up phone calls, and electronic health records, we measured the presence of hazards, removal of hazards, the presence of discharge comprehension issues, and correction or reinforcement of comprehension. These results were validated during home visits by community health workers (CHWs). Feasibility outcomes included patient acceptance of the Transport PLUS intervention and accuracy of the EMT assessment. Qualitative feedback via focus groups was also obtained. Clinical outcomes measured included 3-day and 30-day readmission or ED revisit.

Results

One-hundred three EMTs were trained to administer the intervention and participated in 439 patient encounters. The intervention was determined to be feasible, and patients were highly amenable to the intervention, as evidenced by a 92% and 74% acceptance rate of the DCA and FSA, respectively. The majority of patients also reported that they found the intervention helpful (90%) and self-reported removing 40% of fall hazards; 85% of such changes were validated by CHWs. Readmission/revisit rates are also reported.

Conclusions

The Transport PLUS intervention is a feasible, easily implemented tool in preventative community paramedicine with high levels of patient acceptance. Further study is merited to determine the effectiveness of the intervention in reducing rates of readmission or revisit. A randomized control trial has since begun utilizing the knowledge gained within this study.
Corporate governance looking back to look forward in Pakistan: a review, synthesis and future research agenda
Authors: Khan Sattar , Kamal Yasir , Hussain Shahid , Abbas Muhammad
Published: August 2022

The basic aim of this paper is to systematically review the corporate governance research trends in Pakistan and to give directions for future researchers in this field. The methodology adopted in this paper is “Systematic Literature Review,” 108 papers have been used from the period 2002–2020 along with 17 research theses in this study. The findings of this study show two trends in corporate governance research first one form 2008 to 2016 and the second one is from 2017 to 2020. The first trend shows that corporate governance (variables) is linked with traditional topics such as firm performance, dividend policy, capital structure, cost of capital and earnings management. The theory which is mostly used in the first corporate governance trend is the agency theory. In the second trend, corporate governance (variables) are linked with multiple issues while taking various theoretical perspectives such as risk taking, tunneling, CSR, investment portfolios, board-related issues, financial distress and much more. This paper has identified and filled the research gap by writing a comprehensive review paper of the prevailing corporate governance literature and has given directions for future researchers to consider it. To the best of researchers’ knowledge, this is the first study that has systematically reviewed and synthesized the corporate governance literature by adopting the systematic literature review methodology in Pakistan an emerging economy. It is an extensive effort for the purpose to encourage the interested researchers/scholars to add and expand their contributions to the corporate governance literature in Pakistan on the potentially identified areas of corporate governance.
Prognostic Role of Targeted Methylation Analysis in Paraffin-embedded Samples of Adrenocortical Carcinoma
Authors: Lippert Juliane , Altieri Barbara , Morrison Breanna , Steinhauer Sonja , Smith Gabrielle , Lorey Antonia , Urlaub Hanna , Kircher Stefan , Sitch Alice , Fassnacht Martin , Ronchi Cristina L
Published: August 2022

Context

Adrenocortical carcinoma (ACC) is a rare aggressive disease with heterogeneous prognoses. Previous studies identified hypermethylation in the promoter region of specific genes to be associated with poor clinical outcome.

Objective

Comparative analysis of promising hypermethylated genes as prognostic markers and evaluation of their added value to established clinical prognostic tools.

Design

We included 237 patients with ACCs. Tumor DNA was isolated from formalin-fixed paraffin-embedded (FFPE) samples. Targeted pyrosequencing was used to detect promoter region methylation in 5 preselected genes (PAX5, GSTP1, PYCARD, PAX6, G0S2). The prognostic role of hypermethylation pattern was compared with the Stage, Grade, Resection status, Age, Symptoms (S-GRAS) score. Primary endpoints were progression-free (PFS) and overall survival (OS), with disease-free (DFS) as secondary endpoint.

Results

A total of 27.9%, 13.9%, 49%, 49%, and 25.3% of cases showed hypermethylation in PAX5, GSTP1, PYCARD, PAX6, and G0S2, respectively. Hypermethylation in all individual genes—except GSTP1—was significantly associated with both PFS and OS—with hazard ratios (HR) between 1.4 and 2.3. However, only hypermethylation of PAX5 remained significantly associated with OS (P = 0.013; HR = 1.95, 95% CI, 1.2-3.3) in multivariable analysis. A model for risk stratification was developed, combining PAX5 methylation status and S-GRAS groups, showing improved prognostic performance compared to S-GRAS alone (Harrell’s C index: OS = 0.751, PFS = 0.711, DFS = 0.688).

Conclusions

This study demonstrated that hypermethylation in PAX5 is associated with worst clinical outcome in ACC, even after accounting for S-GRAS score. Assessing methylation in FFPE material is straightforward in the clinical setting and could be used to improve accuracy of prognostic classification, enabling the direction of personalized management.
Child Support and Deadbeat States
Authors: Haney Lynne
Published: August 2022

Drawing on interviews with formerly incarcerated fathers and court observations of child-support hearings, this article explores the state’s role in the massive accumulation of child-support debt. Arguing that this role is too often hidden from view, the article demystifies how much “child” support debt is actually owed to the state itself—and is thus as much about state obligations as familial ones. These state obligations emerge from two main sources: public assistance payback policies, which “bill” noncustodial parents for the cost of the public aid received by their families; and interest charges on all support debt, which most states charge at rates of up to 10 percent. Both state practices hit incarcerated parents especially hard, since they are usually unable to keep up with their support orders while in prison—and often unaware of how and why their debt is accruing. By becoming a means to prop up the state, support debt acts very much like other forms of carceral debt. Yet it also inserts the state into familial relations in ways that can exacerbate conflict between parents and complicate fathers’ ability to care for their children.
Let’s Get Free
Authors: Galindo Manuel , Appel Hannah
Published: August 2022

The majority of people incarcerated in the United States have not been convicted of any crime. Rather, they are there because they are too poor to pay their way out of jail. The financialization of the criminal legal system means that wealthy people go free while poor people suffer through indefinite detention or face an interest-bearing price of freedom: commercial bail bonds contracts, an industry worth more than $2 billion annually. Bail debt is held disproportionately by poor women of color who act as cosigners, bailing out the men in their family who are caged pretrial. The Debt Collective—the nation’s first debtors’ union—is piloting work to abolish $500 million in bail debt held by cosigners across California as a new form of collective action around carceral debt. We explore the concept of a carceral debtors’ union as part of broader debtors’ union and abolition movements.
Nrf2 dictates the neuronal survival and differentiation of embryonic zebrafish harboring compromised alanyl-tRNA synthetase
Authors: Jin Binbin , Xie Liqin , Zhan Dan , Zhou Luping , Feng Zhi , He Jiangyong , Qin Jie , Zhao Congjian , Luo Lingfei , Li Li
Published: August 2022

tRNA synthetase deficiency leads to unfolded protein responses in neuronal disorders; however, its function in embryonic neurogenesis remains unclear. This study identified an aars1cq71/cq71 mutant zebrafish allele that showed increased neuronal apoptosis and compromised neurogenesis. aars1 transcripts were highly expressed in primary neural progenitor cells, and their aberration resulted in protein overloading and activated Perk. nfe2l2b, a paralog of mammalian Nfe2l2, which encodes Nrf2, is a pivotal executor of Perk signaling that regulates neuronal phenotypes in aars1cq71/cq71 mutants. Interference of nfe2l2b in nfe2l2bΔ1/Δ1 mutants did not affect global larval development. However, aars1cq71/cq71;nfe2l2bΔ1/Δ1 mutant embryos exhibited increased neuronal cell survival and neurogenesis compared with their aars1cq71/cq71 siblings. nfe2l2b was harnessed by Perk at two levels. Its transcript was regulated by Chop, an implementer of Perk. It was also phosphorylated by Perk. Both pathways synergistically assured the nuclear functions of nfe2l2b to control cell survival by targeting p53. Our study extends the understanding of tRNA synthetase in neurogenesis and implies that Nrf2 is a cue to mitigate neurodegenerative pathogenesis.
Fate mapping melanoma persister cells through regression and into recurrent disease in adult zebrafish
Authors: Travnickova Jana , Muise Sarah , Wojciechowska Sonia , Brombin Alessandro , Zeng Zhiqiang , Young Adelaide I. J. , Wyatt Cameron , Patton E. Elizabeth
Published: August 2022

Melanoma heterogeneity and plasticity underlie therapy resistance. Some tumour cells possess innate resistance, while others reprogramme during drug exposure and survive to form persister cells, a source of potential cancer cells for recurrent disease. Tracing individual melanoma cell populations through tumour regression and into recurrent disease remains largely unexplored, in part, because complex animal models are required for live imaging of cell populations over time. Here, we applied tamoxifen-inducible creERt2/loxP lineage tracing to a zebrafish model of MITF-dependent melanoma regression and recurrence to image and trace cell populations in vivo through disease stages. Using this strategy, we show that melanoma persister cells at the minimal residual disease site originate from the primary tumour. Next, we fate mapped rare MITF-independent persister cells and demonstrate that these cells directly contribute to progressive disease. Multiplex immunohistochemistry confirmed that MITF-independent persister cells give rise to Mitfa+ cells in recurrent disease. Taken together, our work reveals a direct contribution of persister cell populations to recurrent disease, and provides a resource for lineage-tracing methodology in adult zebrafish cancer models.
Modest increase of KIF11 expression exposes fragilities in the mitotic spindle, causing chromosomal instability
Authors: Dale Katie L. , Armond Jonathan W. , Hynds Robert E. , Vladimirou Elina
Published: August 2022

Chromosomal instability (CIN), the process of increased chromosomal alterations, compromises genomic integrity and has profound consequences on human health. Yet, our understanding of the molecular and mechanistic basis of CIN initiation remains limited. We developed a high-throughput, single-cell, image-based pipeline employing deep-learning and spot-counting models to detect CIN by automatically counting chromosomes and micronuclei. To identify CIN-initiating conditions, we used CRISPR activation in human diploid cells to upregulate, at physiologically relevant levels, 14 genes that are functionally important in cancer. We found that upregulation of CCND1, FOXA1 and NEK2 resulted in pronounced changes in chromosome counts, and KIF11 upregulation resulted in micronuclei formation. We identified KIF11-dependent fragilities within the mitotic spindle; increased levels of KIF11 caused centrosome fragmentation, higher microtubule stability, lagging chromosomes or mitotic catastrophe. Our findings demonstrate that even modest changes in the average expression of single genes in a karyotypically stable background are sufficient for initiating CIN by exposing fragilities of the mitotic spindle, which can lead to a genomically diverse cell population.
The role of neuropeptides in regulating ecdysis and reproduction in the hemimetabolous insect Rhodnius prolixus
Authors: Sterkel Marcos , Volonté Mariano , Albornoz Maximiliano G. , Wulff Juan Pedro , Sánchez Mariana del Huerto , Terán Paula María , Ajmat María Teresa , Ons Sheila
Published: August 2022

In ecdysozoan animals, moulting entails the production of a new exoskeleton and shedding of the old one during ecdysis. It is induced by a pulse of ecdysone that regulates the expression of different hormonal receptors and activates a peptide-mediated signalling cascade. In Holometabola, the peptidergic cascade regulating ecdysis has been well described. However, very little functional information regarding the neuroendocrine regulation of ecdysis is available for Hemimetabola, which display an incomplete metamorphosis. We use Rhodnius prolixus as a convenient experimental model to test two hypotheses: (1) the role of neuropeptides that regulate ecdysis in Holometabola is conserved in hemimetabolous insects; and (2) the neuropeptides regulating ecdysis play a role in the regulation of female reproduction during the adult stage. The RNA interference-mediated reduction of ecdysis triggering hormone (ETH) mRNA levels in fourth-instar nymphs resulted in lethality at the expected time of ecdysis. Unlike in holometabolous insects, knockdown of eth and orcokinin isoform A (oka) did not affect oviposition in adult females, pointing to a different endocrine regulation of ovary maturation. However, eth knockdown prevented egg hatching. The blockage of egg hatching appears to be a consequence of embryonic ecdysis failure. Most of the first-instar nymphs hatched from the eggs laid by females injected with dsRNA for eclosion hormone (dsEH), crustacean cardioactive peptide (dsCCAP) and dsOKA died at the expected time of ecdysis, indicating the crucial involvement of these genes in post-embryonic development. No phenotypes were observed upon corazonin (cz) knockdown in nymphs or adult females. The results are relevant for evolutionary entomology and could reveal targets for neuropeptide-based pest control tools.
Positive psychology pioneers: Ed Diener's power and potential to influence mental health nursing
Authors: Macfarlane Jan
Published: August 2022

This article is the third in a series that celebrates the work of positive psychologists and how their work has the power and potential to influence mental health nursing practice. Focusing on the contribution of Professor Ed Diener (1946–2021), and his work on subjective wellbeing, will help bring interest and understanding to this exciting and developing area of mental health nursing practice.
‘He hits me and that’s just how it is here’: responding to domestic abuse in rural communities
Authors: Barlow Charlotte , Davies Pam , Ewin Rob
Published: August 2022

Few criminological studies have specifically set out to research responses to domestic abuse in rural communities. A small number of recent studies have arrived at the problem from a health and/or social geography perspective lending weight to the increasingly apparent significance of space and culture in rural domestic abuse. This article contributes to this research agenda, focusing on the ways in which police and other agencies respond to domestic abuse within the spatial context of rural England and victim-survivors’ experiences of such responses. The article outlines empirical work with a police partner based in the North of England. The study involved a case file analysis of police data and interviews with police officers, partner agency representatives and victim-survivors. We discuss the ways in which apparent heightened gendered conservatism and the ‘cloak of silence’ leads to difficulties in the identification of domestic abuse in rural communities and argue the importance of engaging in holistic and multi-agency approaches when responding to domestic abuse in remote and inaccessible rural communities.
Women in low intensity political conflict (through the lives of Kashmiri women)
Authors: Majeed Mehak
Published: August 2022

The analysis of gender in conflict and fragile situations is an emerging area of research. Little to no attention has been paid to it up until very recently. There is scant scholarly work available that directly addresses this issue, and there is no research on the relationship between gender and low intensity conflict in Kashmir. It is in this light that the current research note has been written. It traces the broad impact that conflict has had on the lives of women living in the Kashmir region, the conflict centric part of Jammu and Kashmir. Through this research note it is established that the women in Kashmir have been exposed to the shock of unpredicted fragility, and the study is further endorsed by some instantial ethnographic case studies. These shocks have impacted them economically, psychologically and socially. Generations of women have been suffering from the negative impact of the conflict. Alhough disastrous for the most part, women have gradually developed some resilience. With time more and more Kashmiri women have been striving towards gaining economic independence by learning skills, by the acquisition of education and by being gainfully employed.
Polarization-based approach for multipath interference mitigation in time-of-flight imaging
Authors: Zhao Yuwei , Wang Xia , Zhang Yixin , Fang Yujie , Su BingHua
Published: August 2022

The existence of nearby obstruction causes significant errors in depth sensing for time-of-flight cameras, namely multipath interference. A polarized time-of-flight system is established for multipath interference mitigation. Based on polarization cues and the phasor representation of time-of-flight imaging, the proposed method acquires depth maps in high accuracy when specular dominant obstruction is in path. Both rough and smooth targets are applicable in our approach even though they have distinct polarization characteristics. Several experiments with different types of targets and various obstructions confirm the effectiveness of our method qualitatively and quantitatively.
One-step curing process of conductive paste based on a UV pulse laser for a frequency selective surface
Authors: Han Yunlong , Xue Fei , Zhang Pin , Xiao Juanlu
Published: August 2022

A frequency selective surface (FSS) is a two-dimensional periodic array structure, in which a common structure is composed of conductive paste and metal film. An ultraviolet (UV) pulse-laser-induced curing of conductive paste towards FSS was used to simultaneously realize the efficient curing of conductive paste and the removal of surplus materials. Through simple defocus control of the UV pulse laser when irradiating the workpiece, this technology was capable of reducing the energy density and increasing the irradiation range, thus preventing the conductive paste from being ablated and achieving efficient curing. In this context, the curing process of UV curable conductive paste was systematically studied through the Ohmic resistance and bonding force of the cured conductive paste. The curing effects of various conductive paste thicknesses and different laser scanning times at a certain laser scanning speed were also analyzed. The results showed that, after a controllable defocusing treatment, the UV pulse laser could effectively solidify the conductive paste and realize the electrical connection of materials on both sides of the pattern. The peel strength of the conductive paste was greater than 7.1 N/cm. However, the pulse laser curing method needs a longer curing time when compared with the continuous UV curing method.
Double U-groove temperature and refractive index photonic crystal fiber sensor based on surface plasmon resonance
Authors: Zhao Qianhe , Liu Jin , Yang Haima , Liu Haishan , Zeng Guohui , Huang Bo , Jia Jun
Published: August 2022

Based on double U-groove photonic crystal fiber (PCF), a surface plasmon resonance sensor with dual parametric detection of temperature and refractive index is proposed. The birefringence of PCF is increased by using germanium ions doped in the core and introducing U-shaped notches on both sides of the D-shaped fiber. The polished surface of the PCF is coated with gold film and PDMS as a temperature sensing channel, and the U-shaped groove is coated with gold film as a refractive index sensing channel. Through the design of the sensor, it is finally possible to achieve independent measurement of the two parameters. The sensor has a maximum wavelength sensitivity of 4715 nm/RIU in the analyte refractive index range of 1.32–1.4, and maximum wavelength sensitivity of 18 nm/°C in the ambient temperature range of

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30
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C

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50
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. The proposed sensor has broad application prospects in scenarios such as blood analysis, DNA hybridization analysis, and microenvironmental cell interactions.
High contrast, isotropic, and uniform 3D-imaging of centimeter-scale scattering samples using structured illumination light-sheet microscopy with axial sweeping
Authors: Frantz David , Karamahmutoglu Tugba , Schaser Allison J. , Kirik Deniz , Berrocal Edouard
Published: August 2022

Light-sheet fluorescent microscopy (LSFM) has, in recent years, allowed for rapid 3D-imaging of cleared biomedical samples at larger and larger scale. However, even in cleared samples, multiple light scattering often degrades the imaging contrast and widens the optical sectioning. Accumulation of scattering intensifies these negative effects as light propagates inside the tissue, which accentuates the issues when imaging large samples. With axially swept light-sheet microscopy (ASLM), centimeter-scale samples can be scanned with a uniform micrometric optical sectioning. But to fully utilize these benefits for 3D-imaging in biomedical tissue samples, suppression of scattered light is needed. Here, we address this by merging ASLM with light-sheet based structured illumination into Structured Illumination Light-sheet Microscopy with Axial Sweeping (SILMAS). The SILMAS method thus enables high-contrast imaging, isotropic micrometric resolution and uniform optical sectioning in centimeter-scale scattering samples, creating isotropic 3D-volumes of e.g., whole mouse brains without the need for any computation-heavy post-processing. We demonstrate the effectiveness of the approach in agarose gel phantoms with fluorescent beads, and in an PFF injected alpha-synuclein transgenic mouse model tagged with a green fluorescent protein (SynGFP). SILMAS imaging is compared to standard ASLM imaging on the same samples and using the same optical setup, and is shown to increase contrast by as much as 370% and reduce widening of optical sectioning by 74%. With these results, we show that SILMAS improves upon the performance of current state-of-the-art light-sheet microscopes for large and imperfectly cleared tissue samples and is a valuable addition to the LSFM family.