bluuebunny/crossref_metadata_2025 huggingface dataset:
Attenuation of Seizures, Cognitive Deficits, and Brain Histopathology by Phytochemicals of Imperata cylindrica (L.) P. Beauv (Poaceae) in Acute and Chronic Mutant Drosophila melanogaster Epilepsy Models
Authors: Ssempijja Fred , Dare Samuel Sunday , Bukenya Edmund E. M. , Kasozi Keneth Iceland , Kenganzi Ritah , Fernandez Edgar Mario , Vicente-Crespo Marta
Published: March 2023

Imperata cylindrica is a globally distributed plant known for its antiepileptic attributes, but there is a scarcity of robust evidence for its efficacy. The study investigated neuroprotective attributes of Imperata cylindrica root extract on neuropathological features of epilepsy in a Drosophila melanogaster mutant model of epilepsy. It was conducted on 10-day-old (at the initiation of study) male post-eclosion bang-senseless paralytic Drosophila ( parabss1) involved acute (1-3 h) and chronic (6-18 days) experiments; n = 50 flies per group (convulsions tests); n = 100 flies per group (learning/memory tests and histological examination). Administrations were done in 1 g standard fly food, per os. The mutant flies of study ( parabss1) showed marked age-dependent progressive brain neurodegeneration and axonal degeneration, significant (P < 0.05) bang sensitivity and convulsions, and cognitive deficits due to up-regulation of the paralytic gene in our mutants. The neuropathological findings were significantly (P < 0.05) alleviated in dose and duration-dependent fashions to near normal/normal after acute and chronic treatment with extract similar to sodium valproate. Therefore, para is expressed in neurons of brain tissues in our mutant flies to bring about epilepsy phenotypes and behaviors of the current juvenile and old-adult mutant D. melanogaster models of epilepsy. The herb exerts neuroprotection by anticonvulsant and antiepileptogenic mechanisms in mutant D. melanogaster due to plant flavonoids, polyphenols, and chromones (1 and 2) which exert antioxidative and receptor or voltage-gated sodium ion channels’ inhibitory properties, and thus causing reduced inflammation and apoptosis, increased tissue repair, and improved cell biology in the brain of mutant flies. The methanol root extract provides anticonvulsant and antiepileptogenic medicinal values which protect epileptic D. melanogaster. Therefore, the herb should be advanced for more experimental and clinical studies to confirm its efficacy in treating epilepsy.
Diagnostic utility of whole genome sequencing in adults with B-other acute lymphoblastic leukemia
Authors: Leongamornlert Daniel , Gutiérrez-Abril Jesús , Lee SooWah , Barretta Emilio , Creasey Thomas , Gundem Gunes , Levine Max F. , Arango-Ossa Juan E. , Liosis Konstantinos , Medina-Martinez Juan S. , Zuborne Alapi Krisztina , Kirkwood Amy A. , Clifton-Hadley Laura , Patrick Pip , Jones David , O’Neill Laura , Butler Adam P. , Harrison Christine J. , Campbell Peter , Patel Bela , Moorman Anthony V. , Fielding Adele K. , Papaemmanuil Elli
Published: March 2023

Genomic profiling during the diagnosis of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification, and treatment decisions. Patients for whom diagnostic screening fails to identify disease-defining or risk-stratifying lesions are classified as having B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) of paired tumor-normal samples. For 52 patients with B-other, we compared the WGS findings with data from clinical and research cytogenetics. WGS identified a cancer-associated event in 51 of 52 patients, including an established subtype defining genetic alterations that were previously missed with standard-of-care (SoC) genetics in 5 of them. Of the 47 true B-other ALL, we identified a recurrent driver in 87% (41). A complex karyotype via cytogenetics emerges as a heterogeneous group, including distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r and IGK::BCL2). For a subset of 31 cases, we integrated the findings from RNA sequencing (RNA-seq) analysis to include fusion gene detection and classification based on gene expression. Compared with RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes; however, RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrated that WGS can identify clinically relevant genetic abnormalities missed with SoC testing as well as identify leukemia driver events in virtually all cases of B-other ALL.
Plant growth promotion and differential expression of defense genes in chilli pepper against Colletotrichum truncatum induced by Trichoderma asperellum and T. harzianum
Authors: Yadav Mukesh , Divyanshu Kumari , Dubey Manish Kumar , Rai Ashutosh , Kumar Sunil , Tripathi Yashoda Nandan , Shukla Vaishali , Upadhyay Ram Sanmukh
Published: March 2023

Background

Trichoderma asperellum and T. harzianum were assessed in this study as a potential biological control against Colletotrichum truncatum. C. truncatum is a hemibiotrophic fungus that causes anthracnose disease in chilli thereby affecting plant growth and fruit yield. Scanning electron microscope (SEM) technique showed the beneficial interaction between chilli root-Trichoderma spp. inducing the plant growth promotion, mechanical barrier, and defense network under C. truncatum challenged conditions.

Methods

Seeds bio-primed with T. asperellum, T. harzianum, and T. asperellum + T. harzianum promoted the plant growth parameters and strengthening of physical barrier via lignification on the wall of vascular tissues. Seed primed with bioagents were used for exploring the molecular mechanism of defense response in pepper against anthracnose to assess the temporal expression of six defense genes in the Surajmukhi variety of Capsicum annuum. QRT-PCR demonstrated induction of defense responsive genes in chilli pepper bioprimed with Trichoderma spp. such as plant defensin 1.2 (CaPDF1.2), superoxide dismutase (SOD), ascorbate peroxidase (APx), guaiacol peroxidase (GPx), pathogenesis related proteins PR-2 and PR-5.

Results

The results showed that bioprimed seeds were assessed for T. asperellum, T. harzianum, and T. asperellum + T. harzianum-chilli root colonization interaction under in vivo conditions. The results of the scanning electron microscope revealed that T. asperellum, T. harzianum and T. asperellum + T. harzianum interact with chilli roots directly via the development of plant-Trichoderma interaction system. Seeds bio-primed with bioagents promoted the plant growth parameters, fresh and dry weight of shoot and root, plant height, leaf area index, number of leaves, stem diameter and strengthening of physical barrier via lignification on the wall of vascular tissues and expression of six defense related genes in pepper against anthracnose.

Conclusions

Application of T. asperellum and T. harzianum and in combination of treatments enhanced the plant growth. Further, as seeds bioprimed with T. asperellum, T. harzianum and in combination with treatment of T. asperellum + T. harzianum induced the strengthening of the cell wall by lignification and expression of six defense related genes CaPDF1.2, SOD, APx, GPx, PR-2 and PR-5 in pepper against C. truncatum. Our study contributed for better disease management through biopriming with T. asperellum, T. harzianum and T. asperellum + T. harzianum. The biopriming possess enormous potential to promote plant growth, modulate the physical barrier, and induced the defense related genes in chilli pepper against anthracnose.
Antibacterial and anti-biofilm properties of carvacrol alone and in combination with cefixime against Escherichia coli
Authors: Asadi Sepideh , Nayeri-Fasaei Bahar , Zahraei-Salehi Taghi , Yahya-Rayat Ramak , Shams Nemat , Sharifi Aram
Published: March 2023

Background

Plant-derived compounds can be used as antimicrobial agents in medicines and as food preservatives. These compounds can be applied along with other antimicrobial agents to strengthen the effect and/or reduce the required treatment dose.

Results

In the present study, the antibacterial, anti-biofilm and quorum sensing inhibitory activity of carvacrol alone and in combination with the antibiotic cefixime against Escherichia coli was investigated. The MIC and MBC values for carvacrol were 250 μg/mL. In the checkerboard test, carvacrol showed a synergistic interaction with cefixime against E. coli (FIC index = 0.5). Carvacrol and cefixime significantly inhibited biofilm formation at MIC/2 (125 and 62.5 μg/mL), MIC/4 (62.5 and 31.25 μg/mL) and MIC/8 (31.25 and 15.625 μg/mL) for carvacrol and cefixime, respectively. The antibacterial and anti-biofilm potential effect of carvacrol confirmed by the scanning electron microscopy. Real-time quantitative reverse transcription PCR revealed significant down-regulation of the luxS and pfs genes following treatment with a MIC/2 (125 μg/mL) concentration of carvacrol alone and of only pfs gene following treatment with MIC/2 of carvacrol in combination with MIC/2 of cefixime (p < 0.05).

Conclusions

Because of the significant antibacterial and anti-biofilm activity of carvacrol, the present study examines this agent as an antibacterial drug of natural origin. The results indicate that in this study the best antibacterial and anti-biofilm properties are for the combined use of cefixime and carvacrol.
CT texture analysis in predicting treatment response and survival in patients with hepatocellular carcinoma treated with transarterial chemoembolization using random forest models
Authors: An He , Bhatia Inderjeet , Cao Fei , Huang Zilin , Xie Chuanmiao
Published: March 2023

Background

Using texture features derived from contrast-enhanced computed tomography (CT) combined with general imaging features as well as clinical information to predict treatment response and survival in patients with hepatocellular carcinoma (HCC) who received transarterial chemoembolization (TACE) treatment.

Methods

From January 2014 to November 2022, 289 patients with HCC who underwent TACE were retrospectively reviewed. Their clinical information was documented. Their treatment-naïve contrast-enhanced CTs were retrieved and reviewed by two independent radiologists. Four general imaging features were evaluated. Texture features were extracted based on the regions of interest (ROIs) drawn on the slice with the largest axial diameter of all lesions using Pyradiomics v3.0.1. After excluding features with low reproducibility and low predictive value, the remaining features were selected for further analyses. The data were randomly divided in a ratio of 8:2 for model training and testing. Random forest classifiers were built to predict patient response to TACE treatment. Random survival forest models were constructed to predict overall survival (OS) and progress-free survival (PFS).

Results

We retrospectively evaluated 289 patients (55.4 ± 12.4 years old) with HCC treated with TACE. Twenty features, including 2 clinical features (ALT and AFP levels), 1 general imaging feature (presence or absence of portal vein thrombus) and 17 texture features, were included in model construction. The random forest classifier achieved an area under the curve (AUC) of 0.947 with an accuracy of 89.5% for predicting treatment response. The random survival forest showed good predictive performance with out-of-bag error rate of 0.347 (0.374) and a continuous ranked probability score (CRPS) of 0.170 (0.067) for the prediction of OS (PFS).

Conclusions

Random forest algorithm based on texture features combined with general imaging features and clinical information is a robust method for predicting prognosis in patients with HCC treated with TACE, which may help avoid additional examinations and assist in treatment planning.
MicroRNA-125b as a valuable predictive marker for outcome after autologous hematopoietic stem cell transplantation
Authors: Rafiee Mohammad , Amiri Fatemeh , Mohammadi Mohammad Hossein , Hajifathali Abbas
Published: March 2023

Background

Relapse is a frequent occurrence in autologous hematopoietic stem cell transplantation (AHSCT), and early relapse after AHSCT results in poor survival and low quality of life. Predictive marker determination for AHSCT outcomes could be helpful in the prevention of relapse through personalized medicine. Here the predictive value of circulatory microRNAs (miRs) expression for AHSCT outcomes was studied.

Methods

50 MM and lymphoma candidates for AHSCT participated in this study. Two plasma samples were obtained before AHSCT from each candidate; one before mobilization and the other after conditioning. Extracellular vesicles (EVs) were isolated by ultracentrifugation. miR-125b, miR-126, miR-150, and miR-155 expression were analyzed in both plasma and EVs using real time polymerase chain reaction analysis. Other data related to AHSCT and its outcomes were also collected. The predictive value of miRs and other factors for outcomes was assessed by multi-variant analysis.

Results

By 90 weeks follow up after AHSCT, multi-variant and ROC analysis showed miR-125b as a predictive marker for relapse, high lactate dehydrogenase (LDH), and high erythrocyte sedimentation rate (ESR). The cumulative incidence of relapse, high LDH, and high ESR increased with an increase in circulatory miR-125b expression.

Conclusion

miR-125b could be applicable in prognosis evaluation and also create a possible new targeted therapy opportunity for enhanced outcomes and survival after AHSCT.

Trial registration

The study was retrospectively registered. Ethic code No: IR.UMSHA.REC.1400.541.
Predictive value of pigment epithelial detachment markers for visual acuity outcomes in neovascular age-related macular degeneration
Authors: Shu Yiyang , Ye Fuxiang , Liu Haiyun , Wei Jin , Sun Xiaodong
Published: March 2023

Background

To determine the predictive value of quantitative morphological parameters for pigment epithelial detachment (PED) of neovascular age-related macular degeneration (nAMD) patients.

Methods

One eye from each of 159 patients with nAMD were studied. Polypoidal choroidal vasculopathy (PCV) group included 77 eyes, and non-PCV group 82. Patients received conbercept 0.05 ml (0.5 mg) in a 3 + ProReNata (PRN) treatment regimen. Correlations between retinal morphologic parameters at baseline and best-corrected visual acuity (BCVA) gain at 3 or 12 months after treatment (structure–function correlations) were assessed. Optical coherence tomography (OCT) scans were used to assess retinal morphologic features including intraretinal cystoid fluid (IRC), subretinal fluid (SRF), PED or PED type (PEDT), and vitreomacular adhesion (VMA). Greatest height (PEDH) and width of PED (PEDW), and volume of PED (PEDV) at baseline were also measured.

Results

For non-PCV group, BCVA gain from 3 or 12 months after treatment was negatively correlated with PEDV at baseline (r = -0.329, -0.312, P = 0.027, 0.037). BCVA gain at 12 months after treatment was negatively correlated with PEDW at baseline (r = -0.305, P = 0.044). For PCV group, there were no correlations with PEDV, PEDH, PEDW, and PEDT in BCVA gain between baseline and 3 or 12 months after treatment (P > 0.05). SRF, IRC, VMA at baseline did not correlate with short-term and long-term BCVA gain in patients with nAMD (P > 0.05).

Conclusion

For patients with non-PCV, PEDV at baseline was negatively correlated with short-term and long-term BCVA gain, and PEDW was negatively correlated with long-term BCVA gain. On the contrary, quantitative morphological parameters for PED at baseline had no correlation with BCVA gain in patients with PCV.
Effect of anxiety and depression on self-reported adverse reactions to COVID-19 vaccine: a cross-sectional study in Shanghai, China
Authors: Zhou Zhitong , Shen Junwei , Zhao Miaomiao , Zhang Xiaoying , Wang Tao , Li Jue , Zhao Xudong
Published: March 2023

Background

The association of anxiety and depression with adverse reactions after receipt of coronavirus disease 2019 (COVID-19) vaccine is not clear among the general population. This study aims to evaluate the effect of anxiety and depression on self-reported adverse reactions to COVID-19 vaccine.

Methods

The cross-sectional study was conducted during April–July 2021. Participants completing the two doses of vaccine were included in this study. Sociodemographic information, anxiety and depression levels and adverse reactions after the first dose of vaccine for all participants were collected. The anxiety and depression levels were assessed by the Seven-item Generalized Anxiety Disorder Scale and the Nine-item Patient Health Questionnaire Scale, respectively. The multivariate logistic regression analysis was used to examine the association between anxiety and depression and adverse reactions.

Results

A total of 2161 participants were enrolled in this study. The prevalence of anxiety and depression was 13% (95% confidence interval (CI), 11.3–14.2%) and 15% (95%CI, 13.6–16.7%), respectively. Of the 2161 participants, 1607 (74%; 95% CI, 73–76%) reported at least one adverse reaction after the first dose of the vaccine. Pain at the injection site (55%) and fatigue and headache (53% and 18%, respectively) were the most commonly reported local and systemic adverse reactions, respectively. Participants with anxiety or depression or both were more likely to report local and systemic adverse reactions (P < 0.05).

Conclusion

The results suggest that anxiety and depression increase the risk of self-reported adverse reactions to COVID-19 vaccine. Consequently, appropriate psychological interventions before vaccination will help to reduce or alleviate symptoms of vaccination.
Temperament and longitudinal changes in physical activity – the Northern Finland Birth Cohort 1966 Study
Authors: Karppanen Anna-Kaisa , Miettunen Jouko , Hurtig Tuula , Nordström Tanja , Tammelin Tuija , Korpelainen Raija
Published: March 2023

Background

Insufficient physical activity is risk factor for morbidity and premature mortality. This population-based birth cohort study investigated the cross-sectional and longitudinal associations between self-reported temperament at age 31 and self-reported leisure-time moderate to vigorous physical activity (MVPA) levels and changes thereof from the age of 31 to the age of 46 years.

Methods

The study population comprised 3,084 subjects (1,359 male and 1,725 female) from the Northern Finland Birth Cohort 1966. MVPA was self-reported at ages 31 and 46 years. Novelty seeking, harm avoidance, reward dependence, and persistence and their subscales were measured using Cloninger’s Temperament and Character Inventory at age 31. Four temperament clusters were used in the analyses:persistent,overactive,dependent, andpassive. Logistic regression was used to evaluate the relationship between temperament and MVPA.

Results

Thepersistentandoveractivetemperament profiles at age 31 were positively associated with higher MVPA levels both in young adulthood and in midlife, while thepassiveanddependenttemperament profiles were associated with lower MVPA levels. Theoveractivetemperament profile was associated with a decrease in MVPA levels from young adulthood to midlife among males.

Conclusion

Apassivetemperament profile characterized by high harm avoidance is associated with a higher risk of low MVPA level than other temperament profiles over the life cycle in females. The results suggest that temperament may play a role in determining the level and sustainability of MVPA. Individual targeting and intervention tailoring for promoting physical activity should consider temperament traits.
Radical reform of the undergraduate medical education program in a developing country: the Egyptian experience
Authors: Badrawi Nadia , Hosny Somaya , Ragab Lamis , Ghaly Mona , Eldeek Bassem , Tawdi Ahmed F. , Makhlouf Ahmed M. , Said Zeinab N. A. , Mohsen Lamiaa , Waly Amira H. , El-Wazir Yasser
Published: March 2023

Medical educators are in a continuous quest to close the gap between the needs of medical practice and the rising expectations of the communities in their countries. During the past two decades, competency-based medical education has been evolving as an appealing strategy to close this gap. In 2017, the Egyptian medical education authorities mandated all medical schools to change their curricula to comply with revised national academic reference standards, which changed from outcome-based to competency-based. In parallel, they also changed the timeline of all medical programs for six years of studentship and one-year internship to five years and two years, respectively. This substantial reform involved the assessment of the existing situation, an awareness campaign for the proposed changes and an extensive national faculty development program. Monitoring the implementation of this substantial reform was performed through surveys, field visits and meetings with students, teaching staff and program directors. In addition to the expected challenges, the COVID-19-associated restrictions presented a significant further challenge during the implementation of this reform. This article presents the rationale for and steps of this reform, the challenges faced and how they were addressed.
Cultural competence of dutch physician assistants: an observational cohort study
Authors: Leij-Halfwerk Susanne , van Uden Daniëlla , Jooren Sophie J. A. , van den Brink Geert
Published: March 2023

Background

Current cultural competence training needs were assessed as baseline measurement in Dutch physician assistant (PA) students and PA alumni that were not specifically trained in cultural competence. In particular, differences in cultural competency between PA students and PA alumni were assessed.

Methods

In this cross-sectional, observational cohort study knowledge, attitude, and skills and self-perceived overall cultural competence were assessed in Dutch PA students and alumni. Demographics, education and learning needs were collected. Total cultural competence domain scores as well as percentage of maximum scores were calculated.

Results

A total of 40 PA students and 96 alumni (female:75%; Dutch origin:97%) consented to participate. Cultural competence behavior was moderate in both groups. In contrast, general knowledge and exploration of patients’ social context were insufficient, i.e., 53% and 34%, respectively. Self-perceived cultural competence was significantly higher in PA alumni (6.5 ± 1.3, mean ± SD) than in students (6.0 ± 1.3; P < 0.05). Low heterogeneity among PA students and educator exists. Seventy percent of the respondents considers cultural competence important and the majority expressed a need for cultural competence training.

Conclusions

Dutch PA students and alumni have moderate overall cultural competence, but insufficient knowledge and exploring social context. Based on these outcomes the curriculum of the master of science program for physician assistant will be adapted.Emphasis should be made to increase the diversity of PA students to stimulate cross-cultural learning and developing a diverse PA workforce.
The importance of in-country African instructors in International experiential training programs; a qualitative case study from the university of Minnesota
Authors: Nawagi Faith , Raman Aruna
Published: March 2023

Background

For effective delivery of international experiential training programs, many universities in the global north, have created partnerships with universities in the global south especially in Africa to enhance their capacity and diversity of learning for their students. However, there is hardly any literature that exhibits the importance of African instructors in international experiential learning programs. This study aimed at establishing the importance of African instructors in international experiential learning programs.

Methods

This was a qualitative case study that examined the importance of instructors and experts from Africa in influencing student learning processes and outcomes in the GCC 3003/5003 - Seeking Solutions to Global Health Issues. Semi-structured interviews with (2) students, (2) University of Minnesota lead faculty for the course, and (3) in-country instructors/experts from countries in East Africa and the Horn of Africa were conducted. Data was analyzed thematically.

Results

Four themes were identified: (1) Filling gaps in knowledge, (2) Orchestrating partnerships for practical exposure, (3) Improving the quality of training, and (4) orchestrating professional personal growth for students. The African in-country course instructors/experts contributed to student learning by providing a true picture reflection of happenings on the ground.

Conclusion

The importance of in-country African instructors’ can be viewed as that aimed at validating students’ ideas to apply to the local settings, streamlining students’ focus, providing a platform for multi-stakeholder engagement to a particular topic, coupled with bringing an in-country context experience in the classroom.
A six-month prospective, randomised, double-blinded, placebo-controlled, crossover, dietary trial design to investigate the potential of psychobiotics on seizure semiology and comorbidities in canine epilepsy: study protocol
Authors: Schmidt Teresa , Meller Sebastian , Meyerhoff Nina , Twele Friederike , Zanghi Brian , Volk Holger Andreas
Published: March 2023

Background

Epilepsy is the most common chronic neurological disease in dogs. More than two-thirds of these patients suffer from associated behavioural comorbidities. The latter could have their origin in partially overlapping pathomechanisms, with the intestinal microbiome as a potential key link between them. The current arsenal of drugs for epilepsy management remains limited. Most canine patients continue to have seizures despite treatment and the occurrence of comorbidities is not sufficiently addressed, limiting quality of life of affected dogs and owners. Therefore, novel additional epilepsy management options are urgently needed. The microbiome-gut-brain axis may serve as a new target for the development of innovative multimodal therapeutic approaches to overcome current shortcomings in epilepsy management.

Methods

A six-month prospective, randomised, double-blinded, placebo-controlled, crossover, dietary trial was designed to investigate the potential of the psychobioticBifidobacterium longumon behavioural comorbidities in canine epilepsy. Seizure semiology will be evaluated as a secondary outcome measure. Thirty-four privately owned dogs are planned to be included in the ongoing study meeting the following inclusion criteria: Dogs displaying increased anxiety/fear behaviour since the start of the idiopathic epilepsy. Tier II confidence level of the International Veterinary Epilepsy Task Force for the diagnosis of idiopathic epilepsy, with a maximum seizure interval of 3 month and a minimum of three generalised seizures within that period and chronically treated with at least one antiseizure drug without improvement in seizure frequency Each dog will receive the allocated supplement (probiotic vs. placebo) alongside its normal diet for a 3-month period. After a three-week wash out period, the second phase starts by administering the respective other supplement for another 3 months.

Discussion

The current study considers modern high-quality standards for epilepsy medication trials. Common biasing effects should be limited to a possible minimum (regression-to-the mean effect, placebo effect, observer effect), ensuring a high validity and accuracy of the acquired results, thus enabling a representative nature of the efficacy ofBifidobacterium longumas add-on supplement for dogs suffering from epilepsy and its comorbidities. This publication should provide a description of the study procedure and data acquisition methods, including prognosed statistical analysis.
Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming
Authors: Pateras Ioannis S. , Williams Chloe , Gianniou Despoina D. , Margetis Aggelos T. , Avgeris Margaritis , Rousakis Pantelis , Legaki Aigli-Ioanna , Mirtschink Peter , Zhang Wei , Panoutsopoulou Konstantina , Delis Anastasios D. , Pagakis Stamatis N. , Tang Wei , Ambs Stefan , Warpman Berglund Ulrika , Helleday Thomas , Varvarigou Anastasia , Chatzigeorgiou Antonios , Nordström Anders , Tsitsilonis Ourania E. , Trougakos Ioannis P. , Gilthorpe Jonathan D. , Frisan Teresa
Published: March 2023

Background

Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized.

Methods

The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model.

Results

We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model.

Conclusions

Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.
Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies
Authors: Vargas-Soria María , García-Alloza Mónica , Corraliza-Gómez Miriam
Published: March 2023

Diabetes mellitus is a heterogeneous chronic metabolic disorder characterized by the presence of hyperglycemia, commonly preceded by a prediabetic state. The excess of blood glucose can damage multiple organs, including the brain. In fact, cognitive decline and dementia are increasingly being recognized as important comorbidities of diabetes. Despite the largely consistent link between diabetes and dementia, the underlying causes of neurodegeneration in diabetic patients remain to be elucidated. A common factor for almost all neurological disorders is neuroinflammation, a complex inflammatory process in the central nervous system for the most part orchestrated by microglial cells, the main representatives of the immune system in the brain. In this context, our research question aimed to understand how diabetes affects brain and/or retinal microglia physiology. We conducted a systematic search in PubMed and Web of Science to identify research items addressing the effects of diabetes on microglial phenotypic modulation, including critical neuroinflammatory mediators and their pathways. The literature search yielded 1327 records, including 18 patents. Based on the title and abstracts, 830 papers were screened from which 250 primary research papers met the eligibility criteria (original research articles with patients or with a strict diabetes model without comorbidities, that included direct data about microglia in the brain or retina), and 17 additional research papers were included through forward and backward citations, resulting in a total of 267 primary research articles included in the scoping systematic review. We reviewed all primary publications investigating the effects of diabetes and/or its main pathophysiological traits on microglia, including in vitro studies, preclinical models of diabetes and clinical studies on diabetic patients. Although a strict classification of microglia remains elusive given their capacity to adapt to the environment and their morphological, ultrastructural and molecular dynamism, diabetes modulates microglial phenotypic states, triggering specific responses that include upregulation of activity markers (such as Iba1, CD11b, CD68, MHC-II and F4/80), morphological shift to amoeboid shape, secretion of a wide variety of cytokines and chemokines, metabolic reprogramming and generalized increase of oxidative stress. Pathways commonly activated by diabetes-related conditions include NF-κB, NLRP3 inflammasome, fractalkine/CX3CR1, MAPKs, AGEs/RAGE and Akt/mTOR. Altogether, the detailed portrait of complex interactions between diabetes and microglia physiology presented here can be regarded as an important starting point for future research focused on the microglia–metabolism interface.
Scorpionfish rapidly change colour in response to their background
Authors: John Leonie , Santon Matteo , Michiels Nico K.
Published: March 2023

Background

To facilitate background matching in heterogenous environments, some animals rapidly change body colouration. Marine predatory fishes might use this ability to hide from predators and prey. Here, we focus on scorpionfishes (Scorpaenidae), well-camouflaged, bottom-dwelling sit-and-wait predators. We tested whether Scorpaena maderensis and Scorpaena porcus adjust body luminance and hue in response to three artificial backgrounds and thereby achieve background matching. Both scorpionfish species are also red fluorescent, which could contribute to background matching at depth. Therefore, we tested whether red fluorescence is also regulated in response to different backgrounds. The darkest and the lightest backgrounds were grey, while the third background was orange of intermediate luminance. Scorpionfish were placed on all three backgrounds in a randomised repeated measures design. We documented changes in scorpionfish luminance and hue with image analysis and calculated contrast to the backgrounds. Changes were quantified from the visual perspective of two potential prey fishes, the triplefin Tripterygion delaisi and the goby Pomatoschistus flavescens. Additionally, we measured changes in the area of scorpionfish red fluorescence. Because scorpionfish changed quicker than initially expected, we measured luminance change at a higher temporal resolution in a second experiment.

Results

Both scorpionfish species rapidly adjusted luminance and hue in response to a change of background. From prey visual perspective, scorpionfishes’ body achromatic and chromatic contrasts against the background were high, indicating imperfect background matching. Chromatic contrasts differed considerably between the two observer species, highlighting the importance of choosing natural observers with care when studying camouflage. Scorpionfish displayed larger areas of red fluorescence with increasing luminance of the background. With the second experiment, we showed that about 50% of the total luminance change observed after one minute is achieved very rapidly, in five to ten seconds.

Conclusion

Both scorpionfish species change body luminance and hue in response to different backgrounds within seconds. While the achieved background matching was suboptimal for the artificial backgrounds, we propose that the observed changes were intended to reduce detectability, and are an essential strategy to camouflage in the natural environment.
International comparison of pharmaceutical industry payment disclosures in the UK and Japan: implications for self-regulation, public regulation, and transparency
Authors: Ozieranski Piotr , Saito Hiroaki , Rickard Emily , Mulinari Shai , Ozaki Akihiko
Published: March 2023

Background

Self-regulation of payment disclosure by pharmaceutical industry trade groups is a major global approach to increasing transparency of financial relationships between drug companies and healthcare professionals and organisations. Nevertheless, little is known about the relative strengths and weaknesses of self-regulation across countries, especially beyond Europe. To address this gap in research and stimulate international policy learning, we compare the UK and Japan, the likely strongest cases of self-regulation of payment disclosure in Europe and Asia, across three dimensions of transparency: disclosure rules, practices, and data.

Results

The UK and Japanese self-regulation of payment disclosure had shared as well unique strengths and weaknesses. The UK and Japanese pharmaceutical industry trade groups declared transparency as the primary goal of payment disclosure, without, however, explaining the link between the two. The rules of payment disclosure in each country provided more insight into some payments but not others. Both trade groups did not reveal the recipients of certain payments by default, and the UK trade group also made the disclosure of some payments conditional on recipient consent. Drug company disclosure practices were more transparent in the UK, allowing for greater availability and accessibility of payment data and insight into underreporting or misreporting of payments by companies. Nevertheless, the share of payments made to named recipients was three times higher in Japan than in the UK, indicating higher transparency of disclosure data.

Conclusions

The UK and Japan performed differently across the three dimensions of transparency, suggesting that any comprehensive analysis of self-regulation of payment disclosure must triangulate analysis of disclosure rules, practices, and data. We found limited evidence to support key claims regarding the strengths of self-regulation, while often finding it inferior to public regulation of payment disclosure. We suggest how the self-regulation of payment disclosure in each country can be enhanced and, in the long run, replaced by public regulation to strengthen the industry’s accountability to the public.
Access to tablet injectable opioid agonist therapy in rural and smaller urban settings in British Columbia, Canada: a qualitative study
Authors: Bardwell Geoff , Bowles Jeanette M. , Mansoor Manal , Werb Dan , Kerr Thomas
Published: March 2023

Background

Rural and smaller urban settings in Canada are disproportionately impacted by the overdose crisis, highlighting the need for novel public health interventions within these jurisdictions. Tablet injectable opioid agonist therapy (TiOAT) programs have been implemented in select rural communities as a means to address drug-related harms. However, little is known about the accessibility of these novel programs. Therefore, we conducted this study to understand the rural context and factors that affected access of TiOAT programs.

Methods

Between October 2021 to April 2022, individual qualitative semi-structured interviews were conducted with 32 individuals enrolled in a TiOAT program at participating rural and smaller urban sites in British Columbia, Canada. Interview transcripts were coded using NVivo 12 and data were analyzed thematically.

Results

TiOAT access varied considerably. TiOAT delivery in rural settings is complicated due to geographic challenges. Participants who were homeless and staying at a nearby shelter or those in centrally-located supportive housing had minimal issues compared to those living in more affordable housing on the outskirts of town with limited transportation options. Dispensing policies that required daily-witnessed ingestion multiple times daily were challenging for most. Only one site provided evening take-home doses whereas participants at the other site could only resort to the illicit opioid supply to address withdrawal outside of program hours. Participants described the clinics as providing a positive and familial social environment compared to experiences of stigma elsewhere. Medication interruptions did occur when participants were in hospital and custodial settings, leading to withdrawal, program discontinuation, and overdose risk.

Conclusions

This study highlights the beneficial ways in which health services tailored for people who use drugs can create a stigma-free environment with an emphasis on social bonds. Other factors such as transportation access, dispensing policies, and access in rural hospitals and custodial settings produced unique challenges for rural people who use drugs. Public health authorities in rural and smaller settings should consider these factors when designing, implementing, and scaling up future substance use services, including TiOAT programs.
Outcome of patients with soft tissue sarcomas of the extremities and trunk treated by (neo)adjuvant intensity modulated radiation therapy with curative intent
Authors: Dapper Hendrik , Diehl Christian , Knebel Carolin , Mogler Carolin , Borm Kai , Dobiasch Sophie , Combs Stephanie E. , Peeken Jan C.
Published: March 2023

Background

Soft tissue sarcomas (STS) are a relatively rare group of malignant tumors. Currently, there is very little published clinical data, especially in the context of curative multimodal therapy with image-guided, conformal, intensity-modulated radiotherapy.

Methods

Patients who received preoperative or postoperative intensity-modulated radiotherapy for STS of the extremities or trunk with curative intent were included in this single centre retrospective analysis. A Kaplan–Meier analysis was performed to evaluate survival endpoints. Multivariable proportional hazard models were used to investigate the association between survival endpoints and tumour-, patient-, and treatment-specific characteristics.

Results

86 patients were included in the analysis. The most common histological subtypes were undifferentiated pleomorphic high-grade sarcoma (UPS) (27) and liposarcoma (22). More than two third of the patients received preoperative radiation therapy (72%). During the follow-up period, 39 patients (45%) suffered from some type of relapse, mainly remote (31%). The two-years overall survival rate was 88%. The median DFS was 48 months and the median DMFS was 51 months. Female gender (HR 0.460 (0.217; 0.973)) and histology of liposarcomas compared to UPS proved to be significantly more favorable in terms of DFS (HR 0.327 (0.126; 0.852)).

Conclusion

Conformal, intensity-modulated radiotherapy is an effective treatment modality in the preoperative or postoperative management of STS. Especially for the prevention of distant metastases, the establishment of modern systemic therapies or multimodal therapy approaches is necessary.
Calibration procedure and biomechanical validation of an universal six degree-of-freedom robotic system for hip joint testing
Authors: Rychlik Michal , Wendland Georg , Jackowski Michal , Rennert Roland , Schaser Klaus-Dieter , Nowotny Joerg
Published: March 2023

Purpose

Among various test methods for different human joints, the use of robot systems has attracted major interest and inherits the potential to become a gold standard in biomechanical testing in the future. A key issue associated with those robot-based platforms is the accurate definition of parameters, e.g., tool center point (TCP), length of tool or anatomical trajectories of movements. These must be precisely correlated to the physiological parameters of the examined joint and its corresponding bones. Exemplified for the human hip joint, we are creating an accurate calibration procedure for a universal testing platform by using a six degree-of-freedom (6 DOF) robot and optical tracking system for recognition of anatomical movements of the bone samples.

Methods

A six degree-of-freedom robot (TX 200, Stäubli) has been installed and configured. The physiological range of motion of the hip joint composed of a femur and a hemipelvis was recorded with an optical 3D movement and deformation analysis system (ARAMIS, GOM GmbH). The recorded measurements were processed by automatic transformation procedure (created in Delphi software) and evaluated in 3D CAD system.

Results

The physiological ranges of motion were reproduced for all degrees of freedom with the six degree-of-freedom robot in adequate accuracy. With the establishment of a special calibration procedure by using a combination of different coordinate systems, we were able to achieve a standard deviation of the TCP depending of the axis between 0.3 and 0.9 mm and for the length of tool between + 0.67 and − 0.40 mm (3D CAD processing) resp. + 0.72 mm to − 0.13 mm (Delphi transformation). The accuracy between the manual and robotic movement of the hip shows an average deviation between − 0.36 and + 3.44 mm for the points on the movement trajectories.

Conclusion

A six degree-of-freedom robot is appropriate to reproduce the physiological range of motion of the hip joint. The described calibration procedure is universal and can be used for hip joint biomechanical tests allowing to apply clinically relevant forces and investigate testing stability of reconstructive osteosynthesis implant/endoprosthetic fixations, regardless of the length of the femur, size of the femoral head and acetabulum or whether the entire pelvis or only the hemipelvis will be used.
Subtype-specific kinase dependency regulates growth and metastasis of poor-prognosis mesenchymal colorectal cancer
Authors: Buikhuisen Joyce Y. , Gomez Barila Patricia M. , Cameron Kate , Suijkerbuijk Saskia J. E. , Lieftink Cor , di Franco Simone , Krotenberg Garcia Ana , Uceda Castro Rebeca , Lenos Kristiaan J. , Nijman Lisanne E. , Torang Arezo , Longobardi Ciro , de Jong Joan H. , Dekker Daniëlle , Stassi Giorgio , Vermeulen Louis , Beijersbergen Roderick L. , van Rheenen Jacco , Huveneers Stephan , Medema Jan Paul
Published: March 2023

Background

Colorectal cancer (CRC) can be divided into four consensus molecular subtypes (CMS), each with distinct biological features. CMS4 is associated with epithelial-mesenchymal transition and stromal infiltration (Guinney et al., Nat Med 21:1350–6, 2015; Linnekamp et al., Cell Death Differ 25:616–33, 2018), whereas clinically it is characterized by lower responses to adjuvant therapy, higher incidence of metastatic spreading and hence dismal prognosis (Buikhuisen et al., Oncogenesis 9:66, 2020).

Methods

To understand the biology of the mesenchymal subtype and unveil specific vulnerabilities, a large CRISPR-Cas9 drop-out screen was performed on 14 subtyped CRC cell lines to uncover essential kinases in all CMSs. Dependency of CMS4 cells on p21-activated kinase 2 (PAK2) was validated in independent 2D and 3D in vitro cultures and in vivo models assessing primary and metastatic outgrowth in liver and peritoneum. TIRF microscopy was used to uncover actin cytoskeleton dynamics and focal adhesion localization upon PAK2 loss. Subsequent functional assays were performed to determine altered growth and invasion patterns.

Results

PAK2 was identified as a key kinase uniquely required for growth of the mesenchymal subtype CMS4, both in vitro and in vivo. PAK2 plays an important role in cellular attachment and cytoskeletal rearrangements (Coniglio et al., Mol Cell Biol 28:4162–72, 2008; Grebenova et al., Sci Rep 9:17171, 2019). In agreement, deletion or inhibition of PAK2 impaired actin cytoskeleton dynamics in CMS4 cells and, as a consequence, significantly reduced invasive capacity, while it was dispensable for CMS2 cells. Clinical relevance of these findings was supported by the observation that deletion of PAK2 from CMS4 cells prevented metastatic spreading in vivo. Moreover, growth in a model for peritoneal metastasis was hampered when CMS4 tumor cells were deficient for PAK2.

Conclusion

Our data reveal a unique dependency of mesenchymal CRC and provide a rationale for PAK2 inhibition to target this aggressive subgroup of colorectal cancer.