bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation in Melanoma: Impact of Antibiotic Preconditioning on Microbiome and Immunity
Authors: Glitza Isabella C. , Seo Yongwoo David , Spencer Christine N. , Wortman Jennifer R. , Burton Elizabeth M. , Alayli Farah A. , Loo Christopher P. , Gautam Shikha , Damania Ashish , Densmore Julie , Fairchild Justin , Cabanski Christopher R. , Wong Matthew C. , Peterson Christine B. , Weiner Brian , Hicks Nathan , Aunins John , McChalicher Christopher , Walsh Emily , Tetzlaff Michael T. , Hamid Omid , Ott Patrick A. , Boland Genevieve M. , Sullivan Ryan J. , Grossmann Kenneth F. , Ajami Nadim J. , LaVallee Theresa , Henn Matthew R. , Tawbi Hussein A. , Wargo Jennifer A.
Published: July 2024

Abstract
Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials.

Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti–PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.
Pan-RAF:MEK Molecular Glues Take Center Stage
Authors: Hangauer Matthew J. , Gutkind Jorge Silvio , Ferguson Fleur M.
Published: July 2024

In this issue, Ryan and colleagues describe the preclinical development of a pan-RAF:MEK molecular glue with superior efficacy, brain penetrance, and tolerability in xenograft models of Ras/Raf/MAPK pathway–driven tumors.

See related article by Ryan et al., p. 1190 (1).
Circulating Metabolite Profiles and Risk of Coronary Heart Disease Among Racially and Geographically Diverse Populations
Authors: Deng Kui , Gupta Deepak K. , Shu Xiao-Ou , Lipworth Loren , Zheng Wei , Cai Hui , Cai Qiuyin , Yu Danxia
Published: July 2024

BACKGROUND:

Metabolomics may reveal novel biomarkers for coronary heart disease (CHD). We aimed to identify circulating metabolites and construct a metabolite risk score (MRS) associated with incident CHD among racially and geographically diverse populations.

METHODS:

Untargeted metabolomics was conducted using baseline plasma samples from 900 incident CHD cases and 900 age-/sex-/race-matched controls (300 pairs of Black Americans, White Americans, and Chinese adults, respectively), which detected 927 metabolites with known identities among ≥80% of samples. After quality control, 896 case-control pairs remained and were randomly divided into discovery (70%) and validation (30%) sets within each race. In the discovery set, conditional logistic regression and least absolute shrinkage and selection operator over 100 subsamples were applied to identify metabolites robustly associated with CHD risk and construct the MRS. The MRS-CHD association was evaluated using conditional logistic regression and the C-index. Mediation analysis was performed to examine if MRS mediated associations between conventional risk factors and incident CHD. The results from the validation set were presented as the main findings.

RESULTS:

Twenty-four metabolites selected in ≥90% of subsamples comprised the MRS, which was significantly associated with incident CHD (odds ratio per 1 SD, 2.21 [95% CI, 1.62–3.00] after adjusting for sociodemographics, lifestyles, family history, and metabolic health status). MRS could distinguish incident CHD cases from matched controls (C-index, 0.69 [95% CI, 0.63–0.74]) and improve CHD risk prediction when adding to conventional risk factors (C-index, 0.71 [95% CI, 0.65–0.76] versus 0.67 [95% CI, 0.61–0.73];
P
<0.001). The odds ratios and C-index were similar across subgroups defined by race, sex, socioeconomic status, lifestyles, metabolic health, family history, and follow-up duration. The MRS mediated large portions (46.0%–74.2%) of the associations for body mass index, smoking, diabetes, hypertension, and dyslipidemia with incident CHD.

CONCLUSIONS:

In a diverse study sample, we identified 24 circulating metabolites that, when combined into an MRS, were robustly associated with incident CHD and modestly improved CHD risk prediction beyond conventional risk factors.
Systemic Deletion of ARRDC4 Improves Cardiac Reserve and Exercise Capacity in Diabetes
Authors: Nakayama Yoshinobu , Kobayashi Satoru , Masihuddin Aliya , Abdali Syed Amir , Seneviratne A.M. Pramodh Bandara , Ishii Sachiyo , Iida Jun , Liang Qiangrong , Yoshioka Jun
Published: July 2024

BACKGROUND:

Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism.

METHODS:

To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac/skeletal myopathy using cellular and animal models.

RESULTS:

High glucose promoted translocation of MondoA into the nucleus, which upregulated
Arrdc4
transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of
ARRDC4
was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial
Arrdc4
expression in multiple types of mouse models of diabetes. We analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. Deletion of
Arrdc4
augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that
Arrdc4
-knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression using an adenoassociated virus suggests that high levels of myocardial
ARRDC4
have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the
ARRDC4
mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1.

CONCLUSIONS:

ARRDC4 regulates hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.
Ecological Examination of Mortality Rate in an Infant Industry: The Roles of Legitimacy and Illegitimacy
Authors: Li Stan Xiao , Yao Xiaotao , Yang Jie
Published: July 2024

Population ecologists have sidestepped infant industries. Moreover, prior examinations have overlooked the level issue of legitimacy and the role of illegitimacy in firm failure. We suggest that both legitimacy and illegitimacy are potent antecedents of firm failures in an infant industry. We separate industry-level legitimacy from firm-level legitimacy and propose a novel “one-stage model.” This model indicates that incumbents of the infant industry concurrently take actions to advertise their typical and atypical firm features to industry spectators. These actions not only elevate both the industry-level legitimacy of the infant industry and the firm-level legitimacy of the incumbents but also simultaneously incite competition among the incumbents. We used a manually collected database of news articles on Chinese bicycle-sharing companies to examine firm failures in this infant industry from 2014 to 2017. We found that at the industry level, while industry-level legitimacy reduces a firm’s mortality, industry-level illegitimacy elevates the firm’s mortality. At the firm level, we confirm both the detrimental and beneficial effects of interfirm competition. When the rivals of the focal firm tout their atypical firm features, the focal firm’s likelihood of failure increases; when rivals and focal firm try to highlight their typical firm features, the focal firm’s failure rate decreases. When it comes to firm-level illegitimacy, both the focal firm and its rivals’ illegitimacies increase a firm’s mortality. We confirm that legitimacy and illegitimacy are not two poles of a single continuum.
Evaluation of an in-use chest CT protocol in lung cancer screening - A single institutional study
Authors: Naimi Salma , Tetteh Mercy Afadzi , Ashraf Haseem , Johansen Safora
Published: July 2024

Background

Lung cancer is the most common cause of cancer-related death worldwide and therefore there has been a growing demand for low-dose computed tomography (LDCT) protocols.

Purpose

To investigate and evaluate the dose and image quality of patients undergoing lung cancer screening (LCS) using LDCT in Norway.

Materials and Methods

Retrospective dosimetry data, volumetric CT dose index (CTDIvol) and dose-length product (DLP), from 70 average-size and 70 large-size patients who underwent LDCT scan for LCS were included in the survey. Effective dose and size-specific dose were calculated for each examination and were compared with the American Association of Physicists in Medicine (AAPM) requirement. For a quantitative image quality analysis, noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were determined for different regions in the chest with two iterative reconstruction techniques, iDose and Iterative Model Reconstruction. Differences in dose and image quality between average-size and large-size patients were evaluated by Independent sample t test, and Wilcoxon signed rank test within the same patient group.

Results

The independent sample t test revealed significant differences ( p < .05) in dose values between average-size and large-size patients. Mean CTDIvol and DLP for average-size patients were 2.8 mGy and 115 mGy.cm, respectively, with appropriate increment for the large-size patients. Image quality (image noise, SNR, and CNR) did not significantly differ between patient groups when images were reconstructed with a model based iterative reconstruction algorithm.

Conclusion

The screening protocol assessed in this study resulted in CTDIvol values that were compliant with AAPM recommendation. No significant differences in objective image quality were found between patient groups.
Cuticle deposition ceases during strawberry fruit development
Authors: Straube Jannis , Hurtado Grecia , Zeisler-Diehl Viktoria , Schreiber Lukas , Knoche Moritz
Published: July 2024

Background

Ideally, the barrier properties of a fruit’s cuticle persist throughout its development. This presents a challenge for strawberry fruit, with their rapid development and thin cuticles. The objective was to establish the developmental time course of cuticle deposition in strawberry fruit.

Results

Fruit mass and surface area increase rapidly, with peak growth rate coinciding with the onset of ripening. On a whole-fruit basis, the masses of cutin and wax increase but on a unit surface-area basis, they decrease. The decrease is associated with marked increases in elastic strain.

The expressions of cuticle-associated genes involved in transcriptional regulation (FaSHN1, FaSHN2, FaSHN3), synthesis of cutin (FaLACS2, FaGPAT3) and wax (FaCER1, FaKCS10, FaKCR1), and those involved in transport of cutin monomers and wax constituents (FaABCG11, FaABCG32) decreased until maturity. The only exceptions were FaLACS6 and FaGPAT6 that are presumably involved in cutin synthesis, and FaCER1 involved in wax synthesis. This result was consistent across five strawberry cultivars.

Strawberry cutin consists mainly of C16 and C18 monomers, plus minor amounts of C19, C20, C22 and C24 monomers, ω-hydroxy acids, dihydroxy acids, epoxy acids, primary alcohols, carboxylic acids and dicarboxylic acids. The most abundant monomer is 10,16-dihydroxyhexadecanoic acid. Waxes comprise mainly long-chain fatty acids C29 to C46, with smaller amounts of C16 to C28. Wax constituents are carboxylic acids, primary alcohols, alkanes, aldehydes, sterols and esters.

Conclusion

The downregulation of cuticle deposition during development accounts for the marked cuticular strain, for the associated microcracking, and for their high susceptibility to the disorders of water soaking and cracking.
Urdu translation and cross-cultural validation of the stroke self-efficacy questionnaire
Authors: Uroose Waffa , Ikram Mehwish , Ikram Maryam , Shaki ur Rehman Syed , Asif Marvi , Javed Hafiza Rabia
Published: July 2024

Background

The Stroke Self-Efficacy Questionnaire (SSEQ) measures the self-confidence of the individual in functional activities after a stroke. The SSEQ is a self-report scale with 13 items that assess self-efficacy after a stroke in several functional domains.

Objective

The purpose was to translate the Stroke Self-Efficacy Questionnaire into Urdu Language and to find out the validity and reliability of Urdu SSEQ among stroke patients.

Methods

The cross-cultural validation study design was used. Following COSMIN guidelines, forward and backward translation protocols were adopted. After pilot testing on 10 stroke patients, the final Urdu version was drafted. A sample of 110 stroke patients was used to evaluate the validity and reliability of the SSEQ-U. Content and Concurrent validity were determined. The intraclass correlation coefficient and Cronbach’s alpha were used to measure internal consistency and test-retest reliability. Data analysis was performed using SPSS 25.

Results

The final version was drafted after application on 10 stroke patients. Content validity was analyzed by a content validity index ranging from 0.87 to 1. The internal consistency was calculated by Cronbach’s alpha (α > 0.80). Test-retest reliability was determined by the Intra-class correlation coefficient (ICC2,1=0.956). Concurrent validity was determined by correlations with other scales by using the Spearman correlation coefficient; moderate to strong correlations (positive and negative) were found with the Functional Independence Measure (r = 0.76), Beck Depression Inventory (r=-0.54), Short Form of 12-item Scale (r = 0.68) and Fall Efficacy Scale (r = 0.82) with p < 0.05.

Conclusion

The Urdu version was linguistically acceptable and accurate for stroke survivors for determining self-efficacy. It showed good content and concurrent validity, internal consistency and test-retest reliability.
Prevalence and risk factors of food insecurity among Syrian refugees in Türkiye
Authors: Esin Kübra , Işık Tülay , Ayyıldız Feride , Koc Mustafa , Vatanparast Hassan
Published: July 2024

Background

Although Türkiye (Turkey) hosts the largest number of Syrian refugees, studies on food insecurity are limited. This study examined the prevalence and risk factors of food insecurity among Syrian refugees living in Istanbul, which has the highest number of refugees in Türkiye.

Methods

A cross-sectional survey was conducted among Syrian refugees in Istanbul between September 2021 and March 2022. The main income earners of 103 households were interviewed by a research dietitian, with the assistance of an Arabic speaking interpreter through hour-long face-to-face. Data on sociodemographic characteristics (age, gender, nationality, marital status, educational status, the family income, the major source of family income, and the number of family members living in the household etc.) and household food insecurity status were collected. Household food insecurity status was assessed with the eighteen-item Household Food Security Survey Module.

Results

The household food insecurity rate was 90.3%, and those of adults and children were 88.4% and 84.8%, respectively. It was observed that family income level was significantly associated with food insecurity. A one-unit increase in monthly income increased food security by 0.02 times (p < 0.001). The number of employed refugees in the food security group was higher than that in the food insecurity group (p = 0.018). A significant difference was found in the rate of occupation type of the major income earner between the groups (p = 0.046).

Conclusions

High rates of food insecurity, particularly severe food insecurity, were found among Syrian refugees living in Istanbul. While more research is warranted to explore the root causes and efficacy of the current support system, it requires the immediate attention of policymakers at the national and international levels to implement effective policies and interventions.
Exploring acceptability, opportunities, and challenges of community-based home pregnancy testing for early antenatal care initiation in rural Kenya
Authors: Otiso Lilian , Alhassan Yussif , Odhong Tom , Onyango Boniface , Muturi Nelly , Hemingway Charlotte , Murray Lois , Ogwang Emily , Okoth Linet , Oguche Mandela , Doyle Vicki , Fomuso Nadia , Taegtmeyer Miriam
Published: July 2024

Background

Many women in low- and middle-income countries, including Kenya, access antenatal care (ANC) late in pregnancy. Home pregnancy testing can enable women to detect pregnancy early, but it is not widely available. Our study explored the acceptability and potential of home pregnancy testing delivered by community health volunteers (CHV) on antenatal care initiation in rural Kenya.

Methods

This study was part of a public health intervention to improve uptake and quality of ANC. Between November and December 2020, we conducted 37 in-depth interviews involving women who tested positive or negative for a urine pregnancy test provided by CHVs; CHVs and their supervisors involved in the delivery of the pregnancy tests; facility healthcare workers; and key informants. Using Sekhon et al.‘s framework of acceptability, the interviews explored participants’ perceptions and experiences of home pregnancy testing, including acceptability, challenges, and perceived effects on early ANC uptake. Data were analysed thematically in NVivo12 software.

Results

Home pregnancy testing was well-received by women who trusted test results and appreciated the convenience and autonomy it offered. Adolescents cherished the privacy, preferring home testing to facility testing which could be a stigmatising experience. Testing enabled earlier pregnancy recognition and linkage to ANC as well as reproductive decision-making for those with undesired pregnancies. Community delivery of the test enhanced the reputation and visibility of the CHVs as credible primary care providers. CHVs in turn were motivated and confident to deliver home pregnancy testing and did not find it as an unnecessary burden; instead, they perceived it as a complement to their work in providing ANC in the community. Challenges identified included test shortages, confidentiality and safeguarding risks, and difficulties accessing facility-based care post-referral. Newly identified pregnant adolescents hesitated to seek ANC due to stigma, fear of reprimand, unwanted parental notification, and perceived pressure from healthcare workers to keep the pregnancy.

Conclusion

Home pregnancy testing by CHVs can improve early ANC initiation in resource-poor settings. Mitigating privacy, confidentiality, and safeguarding concerns is imperative. Additional support for women transitioning from pregnancy identification to ANC is essential to ensure appropriate care. Future research should focus on integrating home pregnancy testing into routine community health services.
Comparing sexual self-concept in women with obesity pre- and post-bariatric surgery
Authors: Ebadifard Reyhane , Kiani Zahra , Keshavarz Zohreh , Sheikhan Zohre , Alemrajabi Mahdi , Nasiri Maliheh
Published: July 2024

Background

Obesity leads to increased disease burden, decreased life expectancy, and disrupted sexual life. One of the most effective ways of obesity treatment is bariatric surgery. This study was conducted aiming to determine and compare sexual self-concept in women with obesity pre- and post-bariatric surgery.

Method

A longitudinal study comparing sexual self-concept pre and post- surgery was conducted on women with obesity referring to obesity clinics in the city of Tehran in 2020–2021. Data collection was performed using Snell’s Multidimensional Sexual Self-Concept Questionnaire (MSSCQ), which was completed online. Data were analyzed using SPSS version 16 statistical software and Fisher’s exact test, chi-square, Mann-Whitney, independent t, and logistic and linear regression tests. A p-value of less than 0.05 was considered significant.

Results

According to the findings, the mean (standard deviation) score of sexual self-concept was 240.26 (26.82) in the post-surgery group and 200.26 (32.24) in the pre-surgery group (P = 0.001), and the highest mean (standard deviation) score of sexual self-concept both in the pre-surgery group (13.06 [4.00]) and in the post-surgery group (15.46 [2.16]) was related to the area of sexual depression (P = 0.05). Also, with increasing educational level, the odds of bariatric surgery increased by 33%, and those who had no private bedroom had lower odds of bariatric surgery by 65%. In those who did not have other individuals living in their house and their spouse was not a smoker, the self-concept score was 52.35 and 23.11 units higher.

Conclusion

In general, bariatric surgery can improve sexual self-care. Considering the issue of sexual self-concept in bariatric surgery, it is recommended to design appropriate counseling and planning before surgery according to the culture of each country.
Use of poppers (nitrite inhalants) among young men who have sex with men with HIV: A clinic-based qualitative study
Authors: Pepper Nicole , Zúñiga María Luisa , Corliss Heather L.
Published: July 2024

Nitrite inhalants (poppers) are associated with HIV transmission and commonly used among young men who have sex with men (YMSM), a group at increased risk for HIV. Significant research gaps exist in understanding the context in which YMSM use poppers. Qualitative interviews were conducted with 15 YMSM (22–31 years) with HIV to better understand the context in which poppers are used and their impacts on HIV care outcomes, such as care retention and antiretroviral adherence. The Social Ecological Model was applied to understand intrapersonal, interpersonal, community, and system level influences on popper use. Factors influencing popper use included: ubiquity of popper use in sexual settings, introduction to poppers by casual sexual partners, patient-HIV provider communication surrounding poppers, neighborhood, substance use and HIV care systems, and the legal status of poppers. Implications for clinical care, public health, policy, and future research are discussed.
The impact of UK social distancing guidance on the ability to access support and the health and wellbeing of disabled people during the COVID-19 pandemic: a qualitative exploration
Authors: Nicholls Lucy , McKinlay Alison , Berger Rachael , Fancourt Daisy , Burton Alexandra
Published: July 2024

Background

The sudden introduction of social distancing measures in response to the COVID-19 pandemic resulted in significant lifestyle changes for the UK population. People living with physical disabilities were deemed to be at greater risk of complications following COVID-19 infection and were subjected to stricter social distancing guidelines. But gaps remain in our understanding of how the COVID-19 pandemic and associated restrictions affected the ability to access support, health and wellbeing of people with physical disabilities. Such understanding is vital to ensure equitable future pandemic preparedness for people living with physical disabilities.

Methods

We conducted qualitative semi-structured interviews with 31 people living in the UK between May 2020 and January 2022. All participants self-identified as having a physical disability that affected their mobility, sight, or hearing. We analysed the data using reflexive thematic analysis.

Results

Six themes were identified that described the impact of the pandemic on ability to access support, health and wellbeing: (i) adaptations to healthcare provision led to difficulties in managing health and wellbeing; (ii) exacerbations of inequalities in access to public space due to social distancing guidelines; (iii) experiences of hostility from able-bodied people; (iv) loss of social lives and encounters; (v) difficulties maintaining distance from others and subsequent fear of infection and (vi) strategies to support wellbeing and coping when confined to the home.

Conclusion

The COVID-19 pandemic exacerbated existing health and social inequalities experienced by disabled people. The disproportionate impact of the pandemic on service provision and social connections resulted in challenging circumstances for disabled people who faced unmet medical needs, deteriorating health, and at times, hostile public spaces. Disabled people’s experiences need to be incorporated into future pandemic or health-related emergency planning to ensure equality of access to services and public spaces to ensure their health and wellbeing is supported and maintained.
Understanding the challenges of identifying, supporting, and signposting patients with alcohol use disorder in secondary care hospitals, post COVID-19: a qualitative analysis from the North East and North Cumbria, England
Authors: Jackson Katherine , Baker Rosie , O’Donnell Amy , Loughran Iain , Hartrey William , Hulse Sarah
Published: July 2024

Background

Alcohol-related mortality and morbidity increased during the COVID-19 pandemic in England, with people from lower-socioeconomic groups disproportionately affected. The North East and North Cumbria (NENC) region has high levels of deprivation and the highest rates of alcohol-related harm in England. Consequently, there is an urgent need for the implementation of evidence-based preventative approaches such as identifying people at risk of alcohol harm and providing them with appropriate support. Non-alcohol specialist secondary care clinicians could play a key role in delivering these interventions, but current implementation remains limited. In this study we aimed to explore current practices and challenges around identifying, supporting, and signposting patients with Alcohol Use Disorder (AUD) in secondary care hospitals in the NENC through the accounts of staff in the post COVID-19 context.

Methods

Semi-structured qualitative interviews were conducted with 30 non-alcohol specialist staff (10 doctors, 20 nurses) in eight secondary care hospitals across the NENC between June and October 2021. Data were analysed inductively and deductively to identify key codes and themes, with Normalisation Process Theory (NPT) then used to structure the findings.

Results

Findings were grouped using the NPT domains ‘implementation contexts’ and ‘implementation mechanisms’. The following implementation contexts were identified as key factors limiting the implementation of alcohol prevention work: poverty which has been exacerbated by COVID-19 and the prioritisation of acute presentations (negotiating capacity); structural stigma (strategic intentions); and relational stigma (reframing organisational logics). Implementation mechanisms identified as barriers were: workforce knowledge and skills (cognitive participation); the perception that other departments and roles were better placed to deliver this preventative work than their own (collective action); and the perceived futility and negative feedback cycle (reflexive monitoring).

Conclusions

COVID-19, has generated additional challenges to identifying, supporting, and signposting patients with AUD in secondary care hospitals in the NENC. Our interpretation suggests that implementation contexts, in particular structural stigma and growing economic disparity, are the greatest barriers to implementation of evidence-based care in this area. Thus, while some implementation mechanisms can be addressed at a local policy and practice level via improved training and support, system-wide action is needed to enable sustained delivery of preventative alcohol work in these settings.
Recent advances in gene delivery nanoplatforms based on spherical nucleic acids
Authors: Valatabar Nazila , Oroojalian Fatemeh , Kazemzadeh Mina , Mokhtarzadeh Amir Ali , Safaralizadeh Reza , Sahebkar Amirhossein
Published: July 2024

Gene therapy is a therapeutic option for mitigating diseases that do not respond well to pharmacological therapy. This type of therapy allows for correcting altered and defective genes by transferring nucleic acids to target cells. Notably, achieving a desirable outcome is possible by successfully delivering genetic materials into the cell. In-vivo gene transfer strategies use two major classes of vectors, namely viral and nonviral. Both of these systems have distinct pros and cons, and the choice of a delivery system depends on therapeutic objectives and other considerations. Safe and efficient gene transfer is the main feature of any delivery system. Spherical nucleic acids (SNAs) are nanotechnology-based gene delivery systems (i.e., non-viral vectors). They are three-dimensional structures consisting of a hollow or solid spherical core nanoparticle that is functionalized with a dense and highly organized layer of oligonucleotides. The unique structural features of SNAs confer them a high potency in internalization into various types of tissue and cells, a high stability against nucleases, and efficay in penetrating through various biological barriers (such as the skin, blood–brain barrier, and blood–tumor barrier). SNAs also show negligible toxicity and trigger minimal immune response reactions. During the last two decades, all these favorable physicochemical and biological attributes have made them attractive vehicles for drug and nucleic acid delivery. This article discusses the unique structural properties, types of SNAs, and also optimization mechanisms of SNAs. We also focus on recent advances in the synthesis of gene delivery nanoplatforms based on the SNAs.
In situ analysis of neuronal injury and neuroinflammation during HIV-1 infection
Authors: Honeycutt Jenna B. , Wahl Angela , Files Jacob K. , League Alexis F. , Yadav-Samudrala Barkha J. , Garcia J. Victor , Fitting Sylvia
Published: July 2024

Background

Since the introduction of combination antiretroviral therapy (cART) the brain has become an important human immunodeficiency virus (HIV) reservoir due to the relatively low penetration of many drugs utilized in cART into the central nervous system (CNS). Given the inherent limitations of directly assessing acute HIV infection in the brains of people living with HIV (PLWH), animal models, such as humanized mouse models, offer the most effective means of studying the effects of different viral strains and their impact on HIV infection in the CNS. To evaluate CNS pathology during HIV-1 infection in the humanized bone marrow/liver/thymus (BLT) mouse model, a histological analysis was conducted on five CNS regions, including the frontal cortex, hippocampus, striatum, cerebellum, and spinal cord, to delineate the neuronal (MAP2ab, NeuN) and neuroinflammatory (GFAP, Iba-1) changes induced by two viral strains after 2 weeks and 8 weeks post-infection.

Results

Findings reveal HIV-infected human cells in the brain of HIV-infected BLT mice, demonstrating HIV neuroinvasion. Further, both viral strains, HIV-1JR-CSF and HIV-1CH040, induced neuronal injury and astrogliosis across all CNS regions following HIV infection at both time points, as demonstrated by decreases in MAP2ab and increases in GFAP fluorescence signal, respectively. Importantly, infection with HIV-1JR-CSF had more prominent effects on neuronal health in specific CNS regions compared to HIV-1CH040 infection, with decreasing number of NeuN+ neurons, specifically in the frontal cortex. On the other hand, infection with HIV-1CH040 demonstrated more prominent effects on neuroinflammation, assessed by an increase in GFAP signal and/or an increase in number of Iba-1+ microglia, across CNS regions.

Conclusion

These findings demonstrate that CNS pathology is widespread during acute HIV infection. However, neuronal loss and the magnitude of neuroinflammation in the CNS is strain dependent indicating that strains of HIV cause differential CNS pathologies.
From balance to imbalance: disruption of plasma glutathione concentration in micropapillary thyroid carcinoma
Authors: Eskandari Fatemeh , Hedayati Mehdi , Tavangar S. Mohammad , Rezaei Farnaz , Khodagholipour Afsaneh , Razavi S. Adeleh
Published: July 2024

Background

Despite the presence of evidence that establishes a strong correlation between oxidative stress and thyroid cancer, there exists a scarcity of research that investigates the specific role of glutathione as an important antioxidant in this particular context. The objective of this study was to assess the altered balance of oxidative stress in cases of thyroid cancer, which includes both papillary thyroid carcinoma (PTC) and micro PTC (mPTC), by examining and comparing the total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), reduced glutathione (GSH), oxidized glutathione (GSSG), and GSSG/GSH ratio with those of individuals diagnosed with multinodular goiter (MNG) as well as Healthy subjects.

Materials and methods

Plasma samples were collected from 92 patients (23 mPTC, 23 PTC, 23 MNG, 23 Healthy). The levels of TAC, TOS, GSH, and GSSG were measured using a commercial assay kits, and the OSI and GSSG/GSH ratio were calculated for each sample. Statistical analyses were performed to compare the oxidative stress between the groups.

Results

The plasma levels of TOS were significantly higher in the mPTC, PTC, and MNG groups compared to the Healthy individuals (p < 0.05). The OSI in the mPTC and PTC groups showed a significant increase compared to the Healthy group (p < 0.05). The levels of GSH in mPTC and PTC were markedly lower compared to the Healthy subjects (p < 0.01). Interestingly, the concentration of GSH in mPTC was found to be considerably lower than in PTC and MNG patients (p < 0.01).

Conclusion

These findings indicate that GSH may be a useful biomarker for evaluating oxidative stress and antioxidant system status in patients with PTC, especially mPTC. Low levels of GSH may indicate increased levels of oxidative stress, which may contribute to the development and progression of mPTC to PTC.
Monitoring changing patterns in HER2 addiction by liquid biopsy in advanced breast cancer patients
Authors: Giordani Elena , Allegretti Matteo , Sinibaldi Alberto , Michelotti Francesco , Ferretti Gianluigi , Ricciardi Elena , Ziccheddu Giovanna , Valenti Fabio , Di Martino Simona , Ercolani Cristiana , Giannarelli Diana , Arpino Grazia , Gori Stefania , Omarini Claudia , Zambelli Alberto , Bria Emilio , Paris Ida , Buglioni Simonetta , Giacomini Patrizio , Fabi Alessandra
Published: July 2024

Background

During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D.

Methods

aHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1).

Results

As expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009).

Conclusions

HER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors.

Trial registration

NCT05735392 retrospectively registered on January 31, 2023 https://www.clinicaltrials.gov/search?term=NCT05735392
Utilizing human cerebral organoids to model breast cancer brain metastasis in culture
Authors: Wang Chenran , Nagayach Aarti , Patel Harsh , Dao Lan , Zhu Hui , Wasylishen Amanda R. , Fan Yanbo , Kendler Ady , Guo Ziyuan
Published: July 2024

Background

Metastasis, the spread, and growth of malignant cells at secondary sites within a patient’s body, accounts for over 90% of cancer-related mortality. Breast cancer is the most common tumor type diagnosed and the leading cause of cancer lethality in women in the United States. It is estimated that 10–16% breast cancer patients will have brain metastasis. Current therapies to treat patients with breast cancer brain metastasis (BCBM) remain palliative. This is largely due to our limited understanding of the fundamental molecular and cellular mechanisms through which BCBM progresses, which represents a critical barrier for the development of efficient therapies for affected breast cancer patients.

Methods

Previous research in BCBM relied on co-culture assays of tumor cells with rodent neural cells or rodent brain slice ex vivo. Given the need to overcome the obstacle for human-relevant host to study cell-cell communication in BCBM, we generated human embryonic stem cell-derived cerebral organoids to co-culture with human breast cancer cell lines. We used MDA-MB-231 and its brain metastatic derivate MDA-MB-231 Br-EGFP, other cell lines of MCF-7, HCC-1806, and SUM159PT. We leveraged this novel 3D co-culture platform to investigate the crosstalk of human breast cancer cells with neural cells in cerebral organoid.

Results

We found that MDA-MB-231 and SUM159PT breast cancer cells formed tumor colonies in human cerebral organoids. Moreover, MDA-MB-231 Br-EGFP cells showed increased capacity to invade and expand in human cerebral organoids.

Conclusions

Our co-culture model has demonstrated a remarkable capacity to discern the brain metastatic ability of human breast cancer cells in cerebral organoids. The generation of BCBM-like structures in organoid will facilitate the study of human tumor microenvironment in culture.
RIBAP: a comprehensive bacterial core genome annotation pipeline for pangenome calculation beyond the species level
Authors: Lamkiewicz Kevin , Barf Lisa-Marie , Sachse Konrad , Hölzer Martin
Published: July 2024

Microbial pangenome analysis identifies present or absent genes in prokaryotic genomes. However, current tools are limited when analyzing species with higher sequence diversity or higher taxonomic orders such as genera or families. The Roary ILP Bacterial core Annotation Pipeline (RIBAP) uses an integer linear programming approach to refine gene clusters predicted by Roary for identifying core genes. RIBAP successfully handles the complexity and diversity of Chlamydia, Klebsiella, Brucella, and Enterococcus genomes, outperforming other established and recent pangenome tools for identifying all-encompassing core genes at the genus level. RIBAP is a freely available Nextflow pipeline at github.com/hoelzer-lab/ribap and zenodo.org/doi/10.5281/zenodo.10890871.
High expression of serine protease, Brachyurin in the posterior midgut of black soldier fly (Hermetia illucens) during horse dropping processing
Authors: Wakuda Megumi , Sakamoto Takuma , Tanaka Akane , Sugimura Satoshi , Higashiura Yuki , Nakazato Takeru , Bono Hidemasa , Tabunoki Hiroko
Published: July 2024

Objective

Livestock droppings cause some environmental problems, but they have the potential to be used as effective biomass resources. The black soldier fly (BSF), Hermetia illucens (Diptera: Stratiomyidae), is suitable for efficiently processing such resources. By using BSF larvae for the disposal of livestock droppings, we can obtain two valuable products: protein resources and organic fertilizer. However, there is insufficient research on the digestive enzymes suitable for processing this waste. Here, we aimed to construct an efficient BSF processing system using livestock droppings, and we explored the digestive enzymes involved in this process.

Results

First, we investigated the characteristics of transcripts expressed in the midgut of BSF larvae and found that immune response-related genes were expressed in the midgut. Then, we investigated digestive enzymes and identified a novel serine protease, HiBrachyurin, whose mRNA was highly expressed in the posterior midgut when BSF larvae fed on horse droppings. Despite the low protein content of horse droppings, larvae that fed on horse droppings accumulated more protein than those in the other groups. Therefore, HiBrachyurin may contribute to digestibility in the early stage of protein degradation in BSF larvae fed on horse droppings.
Optimizing chitosan derived from Metapenaeus affinis: a novel anti-biofilm agent against Pseudomonas aeruginosa
Authors: Riahi Anali , Mabudi Hadideh , Tajbakhsh Elahe , Roomiani Laleh , Momtaz Hasan
Published: July 2024

Pseudomonas aeruginosa is a commonly found Gram-negative bacterium in healthcare facilities and is renowned for its ability to form biofilms and its virulence factors that are controlled by quorum sensing (QS) systems. The increasing prevalence of multidrug-resistant strains of this bacterium poses a significant challenge in the field of medicine. Consequently, the exploration of novel antimicrobial agents has become a top priority. This research aims to optimize chitosan derived from white shrimp (Metapenaeus affinis) using the Response Surface Methodology (RSM) computational approach. The objective is to investigate chitosan’s potential as a solution for inhibiting QS activity and biofilm formation in P. aeruginosa ATCC 10,145. Under optimized conditions, chitin was treated with NaOH (1.41 M) for 15.75 h, HCl (7.49% vol) for 2.01 h, and at a deacetylation temperature of 81.15 °C. The resulting chitosan exhibited a degree of deacetylation (DD%) exceeding 93.98%, as confirmed by Fourier-transform infrared (FTIR) spectral analysis, indicating its high purity. The extracted chitosan demonstrated a significant synergistic antibiotic effect against P. aeruginosa when combined with ceftazidime, enhancing its bactericidal activity by up to 15-fold. In addition, sub-MIC (minimum inhibitory concentration) concentrations of extracted chitosan (10 and 100 µg/mL) successfully reduced the production of pyocyanin and rhamnolipid, as well as the swimming motility, protease activity and biofilm formation ability in comparison to the control group (P < 0.05). Moreover, chitosan treatment downregulated the RhlR and LasR genes in P. aeruginosa when compared to the control group (P < 0.05). The optimized chitosan extract shows significant potential as a coating agent for surgical equipment, effectively preventing nosocomial infections caused by P. aeruginosa pathogens.
Entry of ZSWIM4 to the nucleus is crucial for its inhibition of KIT and BMAL1 in gastrointestinal stromal tumors
Authors: Cao Xu , Tian Jinhai , Cheung Man Yee , Zhang Liangying , Liu Zimei , Jiang Zongying , Zhang Shaoting , Xiao Kun , Zhao Sien , Wang Ming , Ding Feng , Li Shujing , Ma Lijun , Zhao Hui , Sun Jianmin
Published: July 2024

Background

Zinc finger SWIM-type containing 4 (ZSWIM4) is a zinc finger protein with its function largely uncharacterized. In this study, we aimed to investigate the role of ZSWIM4 in gastrointestinal stromal tumors (GISTs).

Results

We found that ZSWIM4 expression is inhibited by the predominantly mutated protein KIT in GISTs, while conversely, ZSWIM4 inhibits KIT expression and downstream signaling. Consistent with the observation, ZSWIM4 inhibited GIST cell survival and proliferation in vitro. RNA sequencing of GISTs from KITV558A/WT mice and KITV558A/WT/ZSWIM4−/− mice showed that loss of ZSWIM4 expression increases the expression of circadian clock pathway member BMAL1 which contributes to GIST cell survival and proliferation. In addition, we found that KIT signaling increases the distribution of ZSWIM4 in the nucleus of GIST cells, and which is important for its inhibition of KIT and BMAL1. In agreement with the results in vitro, the in vivo studies showed that ZSWIM4 deficiency increases the tumorigenesis of GISTs in KITV558A/WT mice.

Conclusions

Taken together, our results revealed that the entry of ZSWIM4 to the nucleus is important for its inhibition of KIT and BMAL1, ultimately attenuating GIST tumorigenesis. The results provide a novel insight in the understanding of signal transduction in GISTs and lay strong theoretical basis for the advancement of GIST treatment.