bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution of High-Affinity ssDNA Sequence to Carbon Nanotube
Authors: Lee Dakyeon , Jeong Sanghwa
Published: September 2023

Colloidal ssDNA-wrapped single walled carbon nanotube (ssDNA-SWCNT) has been used as the second near-infrared (NIR-II, 1000 -1700 nm) fluorescent nanoprobes with outstanding biocompatibility, and acts as various optical nano sensors for biological analytes such as a dopamine and serotonin. The stability and affinity of ssDNA on the SWCNT surface significantly depends on the sequence of ssDNA, however the large-scale quantitative analysis between ssDNA sequence library, which has high affinity to the SWCNT surface, was repeatedly selected from a random ssDNA(N30) library (~1018) and the resulting sequence data was analyzed. The binding affinity of ssDNA to SWCNT was quantitatively characterized. To quantitatively analyze the kinetics of the process which occurs solvatochromic shift by sodium cholate, assumed the dynamics follow a first-order kinetic model and fit the experimental data using exponential regression, from which decay time constants were determined. As a result, the highest binding affinity of ssDNA to SWCNT was quantitatively characterized by time constant (1.5 X106 sec) which increased by 100 times compared to the N30 random library. Through analysis of the ssDNA sequences with high affinity for the SWCNT surface, we found that the sequences contain high contents of cytosine and adenine nucleotides and complementary base pairs appeared at distance of 5 to 8 bases. This novel sequence library can be applied for the preparation of the ultra-stable ssDNA-SWCNT dispersion and used for anchoring surface ligands for SWCNT as biosensor.

Figure 1
Effects of in utero exposure to fluoxetine on the gastrointestinal tract of rat offspring
Authors: Prowse Katherine L. , Law Harriet , Raez-Villanueva Sergio , Markovic Filip , Wang Megan , Borojevic Rajka , Parsons Sean P. , Vincent Alexander D. , Holloway Alison C. , Ratcliffe Elyanne M.
Published: September 2023

There is increasing recognition of the relevance of in utero and early postnatal exposures in the developmental programming of the gastrointestinal tract. Perinatal exposure to selective serotonin reuptake inhibitors and antidepressant medications is of particular relevance as they are commonly prescribed during pregnancy, and serotonergic pathways play key roles during gastrointestinal development and in postnatal homeostasis. Here, we provide a comprehensive evaluation of clinically relevant outcomes of gastrointestinal motility and susceptibility to colitis in fluoxetine-exposed offspring and highlight changes in colonic serotonergic neurons at the peak of perinatal fluoxetine exposure with sex-dependent changes in serotonin signaling and colonic motility in adulthood.
The hemodynamic interplay between pulmonary ischemia-reperfusion injury and right ventricular function in lung transplantation: a translational porcine model
Authors: Orlitová Michaela , Verbelen Tom , Frick Anna E. , Vanstapel Arno , Van Beersel Dieter , Ordies Sofie , Van Slambrouck Jan , Kaes Janne , Jin Xin , Coudyzer Walter , Verleden Stijn E. , Verleden Geert M. , Vanaudenaerde Bart M. , Van Raemdonck Dirk E. , Vos Robin , Ceulemans Laurens J. , Claus Piet , Neyrinck Arne P.
Published: September 2023

In contrast to the abundant literature of mechanical pulmonary artery clamping to increase right ventricular afterload, we developed a model adding a biological factor of pulmonary ischemia-reperfusion injury. We did not only focus on the right ventricular behavior, but also on the interaction with the injured lung. We are the first to describe this interaction while addressing the hemodynamic intraoperative phases of clinical lung transplantation.
Multibiomass and Natural Marine Waste Catalyst Copyrolysis: Exploring Synergy, Isoconversional Kinetics, Thermodynamics, and Mechanism
Authors: Mariyam Sabah , Al-Ansari Tareq , McKay Gordon
Published: September 2023

This study presents the copyrolysis of three biomasses (date pits, cow manure, and coffee waste) and explores the potential of utilizing natural waste catalysts—seashell (SS) and cuttlebone (CB)—to improve the kinetics and thermodynamics of the process. Mixing the feeds led to positive synergistic effects, particularly at a heating rate of 10 K/min or higher. By employing three model-free kinetic methods, the estimated activation energy (Ea) was lower for the ternary feed than the single feeds, and 20 wt.% of the feed with SS and CB catalysts was added. The Ea reduced from 162 kJ/mol for the ternary feed by 25.6% (~121 kJ/mol) and 21.6% (154 kJ/mol) in the presence of SS and CB, respectively. The thermodynamic parameters were positive for all the noncatalytic feeds, resulting in endothermic, nonspontaneous reactions and increased disorder or randomness. Catalysts influenced the thermodynamic parameters, making the process more energy efficient. The results are the utilization of cheap, eco-friendly feeds and catalysts for sustainable energy production using copyrolysis.
Effectiveness of Psychoeducation on Burden among Family Caregivers of Adults with Schizophrenia: A Systematic Review and Meta-Analysis
Authors: Okafor Akunna Jane , Monahan Mark
Published: September 2023

Caring for relatives living with schizophrenia could lead to caregivers’ burden. It is believed that lack of information and understanding about schizophrenia and lack of skills to cope effectively while caring for their adult relatives largely contribute to the burden they experience. The burden is assessed using assessment scales. This review aims to assess the effectiveness of psychoeducation in alleviating the burden experienced by family caregivers of adults living with schizophrenia and to identify essential factors that facilitate positive outcomes. Five databases (ASSIA, CINAHL, Embase, MEDLINE EBSCO, and PsycINFO) were systematically searched using combinations of the following key terms: “family caregivers,” “schizophrenia,” “burden,” “psychoeducation,” and “adults.” Meta-analysis of included studies was conducted using RevMan 5.4. Five RCTs with 320 family caregivers were included in the review. Overall, none of the studies showed a low risk of bias. The evidence suggests that face-to-face group psychoeducation reduced family caregivers’ burden when measured across different time points: one-week postintervention (mean difference −3.87 and Cl −6.06 to −1.70), six months (MD −8.76 and Cl −12.38 to −5.13), and twelve months (MD −7.38 and Cl −9.85 to −4.91). Measurements immediately after the intervention, one month, and three months postintervention when reported narratively also showed a reduction in family caregivers’ burden. Face-to-face group psychoeducation provided for family caregivers effectively alleviates the burden they experience. Factors such as program content and teaching methods facilitated positive outcomes. It is recommended that psychoeducation should be integrated as a routine intervention for family caregivers.
Exploration of an On-Site Pharmacist Intervention within Australian Residential Aged Care Facilities Using Normalisation Process Theory: A Mixed-Methods Study
Authors: Batten Miranda , Kosari Sam , Lewis Joanne , Naunton Mark , Strickland Karen
Published: September 2023

Residents living in residential aged care facilities (RACFs) continue to experience medication-related harm. There is ongoing interest in expanding the role of pharmacists, including on-site pharmacists (OSPs), to help improve medication management in RACFs. The objectives of this mixed-methods study were to explore the extent and ways in which on-site pharmacists (OSPs) were normalised within RACFs as part of a complex intervention seeking to improve medication management. This study consisted of semistructured interviews informed by normalisation process theory (NPT) and a quantitative survey adapted from the normalisation measure development questionnaire (NoMAD) instrument which is underpinned by NPT. Semistructured interviews with prescribers, RACF managers, RACF nursing staff, OSPs, residents, and family members (n = 47) indicated that most participants supported OSPs within RACFs that having OSPs in RACFs made sense and was perceived as beneficial and that participants were invested in working with OSPs who often became part of routine practice, i.e., “normalised.” Prescribers, RACF managers, and nursing staff (health care team members) completed the adapted survey, and their responses (n = 16) strongly complemented the positive qualitative findings. Overall, OSPs were positively appraised by health care team members as well as residents and family members and were generally considered to be normalised within their respective RACFs. This study explored the normalisation of OSPs within RACFs. From the perspective of residents, family members, health care team members, and OSPs, OSPs could become part of routine practice within Australian RACFs. The findings of this study also highlighted the value of using theory to guide the evaluation of a pharmacist intervention in RACFs and the utility of applying NPT in a new setting, Australian RACFs. Importantly, the findings of this study could help inform the future role of OSPs working and the rollout of OSPs within Australian RACFs.
Optimizing Artemia Enrichment: A Low DHA/High EPA Protocol for Enhanced n-3 LC-HUFA Levels to Support Greater Amberjack (Seriola dumerili) Larval Rearing
Authors: Roo Javier , Montero Daniel , Raquel Quirós-Pozo , Monzón-Rivero Christian , Izquierdo López Marisol
Published: September 2023

Most commercial products available for Artemia sp. enrichment include high levels of docosahexaenoic acid (DHA) to boost its nutritional value, though with limited success. In this regard, the present study evaluated the alternative utilization of eicosapentaenoic acid (20 : 5n-3; EPA) oils to improve the n-3 long-chain highly unsaturated fatty acid content (n-3 LC-HUFA) in enriched Artemia sp. to feed greater amberjack (Seriola dumerili) larvae. Five experimental emulsions containing increasing levels of EPA from 0.8% to 60% of total fatty acids (TFA) and n-3 LC-HUFA (1.3%–70.6% TFA) were formulated. Each diet was fed to greater amberjack larvae (17–35 days posthatch (dph)) in three replicate 200-L tanks. The dietary EPA supplementation significantly improved larval growth during the feeding trial and survival at 35 dph (

P
<
0.05

). In addition, larval fatty acid profiles showed a positive correlation with dietary EPA. Finally, despite the sum of total skeletal anomalies and column anomalies were not significantly affected by dietary EPA, increasing dietary EPA, and n-3 LC-HUFA tended to reduce the incidence of these types of anomalies in greater amberjack larvae at 35 dph. Based on these results, S. dumerili larvae could be successfully grown with low DHA but high EPA-rich oil enrichment products when n-3 LC-HUFA content in Artemia sp. is maintained in sufficient amounts.
Relationship between Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Hyperhomocysteinemia in Patients with Ischemic Stroke: A Proof-of-Concept Randomized Trial
Authors: Luo Bing , Wang Yun , Sun Minjie , Feng Mei , Zhu Wei , Xu Sufang
Published: September 2023

Background. This study is aimed at investigating the relationship between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and hyperhomocysteinemia (HHCY) in patients with ischemic stroke (IS). Methods. This study retrospectively analyzed the clinical data and laboratory results of 110 IS patients. According to the cut-off value of

HCY
=
15
 
μ
mol
/
L

, the included patients were divided into the normal HCY (NHCY,

n
=
69

) and the high HCY (HHCY,

n
=
41

) groups. The relationship between NLR, PLR, and HCY between these groups was then compared. Results. NLR and PLR levels in IS patients with HHCY were significantly higher than those in IS patients without HHCY (

P
<
0.05

). Correlation analysis showed that NLR and PLR were positively correlated with hs-CRP, RDW, N, L, and HCY (

P
<
0.05

). NLR and PLR were the largest predictors of IS-related HHCY, followed by WBC, hs-CRP, RDW, VLDL, and TG. Additionally, NLR and PLR were independent risk factors for IS-related HHCY. Conclusions. NLR and PLR may be fast, cheap, and easy-to-analyze biomarkers for predicting IS-related HHCY.
miR-325-3p Reduces Proliferation and Promotes Apoptosis of Gastric Cancer Cells by Inhibiting Human Antigen R
Authors: Huang Zhengwei , Luo Yacan , Chen Congcong , Zhou Chaoyang , Su Zhengkang , Cai Chang , Li Xi , Wu Wenzhi
Published: September 2023

Human antigen R (HuR), also known as ELAVL1, is a widely expressed RNA-binding protein (RBP) that has a significant impact on the development and advancement of tumors. Our previous study found that 5-fluorouracil (5-FU) may impede the proliferation and increase apoptosis in gastric cancer cells by reducing the nucleocytoplasmic shuttling of HuR. However, how posttranscriptional regulation influences HuR functions in gastric cancer remains to be elucidated. Here, we demonstrated that miR-325-3p has the potential to regulate the expression level of HuR by directly binding to its 3′UTR, which in turn led to a significant reduction in proliferation and an increase in apoptosis in gastric cancer cells. In addition, xenograft experiment showed that knockdown of HuR or overexpression of miR-325-3p group exhibited smaller tumor sizes after transplant of gastric cancer cells into zebrafish larvae. Thus, our findings offer new insights into the pathogenesis of gastric cancer and may potentially assist in identifying novel targets for drug therapy.
Growth Modification of Developing Class II Division 1 Malocclusion Using Myofunctional Appliances
Authors: Alhasyimi Ananto Ali , Syahfik Iman
Published: September 2023

Background and Overview. Interceptive orthodontics is a phase of orthodontics that identifies and corrects potential malocclusions in the growing dentofacial complex. At this point, myofunctional appliances are a necessary component. A 9-year-old girl appeared with a Class II division 1, a 6 mm overjet, a 6 mm overbite, a V-shaped maxillary arch, as well as lip hypertonicity, and an overdeveloped maxilla. Myobrace® combines the dental alignment abilities of rigid and soft appliances. Its structure replicates a fixed appliance: the soft outer part acts as the orthodontic wire, whereas the inner hard part engages the teeth individually. After 12 months of treatment, facial photos and a cephalogram were taken, both of which demonstrated an enhancement to the patient’s facial profile. Conclusions and Practical Implications. This case demonstrates that Myobrace® may be a simple and good choice to treat skeletal malocclusion with oral habit because of its greater compliance and favorable results. In certain instances, an early approach, taking into account patient preferences and compliance, is practical and should be considered in future treatment planning and research.
Impact of Pesticides on Diversity and Abundance of Predatory Arthropods in Rice Ecosystem
Authors: Raut A. M. , Banu A. Najitha , Akram Waseem , Nain Rohit Singh , Singh Karan , Wahengabam Johnson , Shankar Chitra , Shah Mohd Asif
Published: September 2023

Rice (Oryza sativa) is one of the most important cereal crops with a diverse set of pests and natural enemies. Rice fields often support a high diversity of arthropods which contribute significantly to productivity. This diversity is frequently threatened due to indiscriminate applications of pesticides. Our aim was to emphasize on the predator diversity in agrochemical exposed rice field as well as on the impact of surrounding vegetation on beneficial insect diversity. Natural enemies’ data were recorded from randomly selected 10 quadrates by visual observation from each treatment. A total of 5,590 individuals of predators were observed during the study period which included 27 species belonging to 16 families from five orders of arthropods during the kharif season of rice. Statistically, there were no significant differences between the population of general natural enemies such as Odonata, Coleoptera, Hymenoptera, and Araneae in plots with insecticide and control during the different growth stages of rice cultivation. Diversity indices were almost similar in fields where pesticide was sprayed and not sprayed. Our study concluded that natural enemies are conserved by ensuring crop heterogeneity, growing insect-friendly plants (with high levels of nectar and pollen) as border crops, and judicious application of granule insecticide like cartap hydrochloride in a rice agro-ecosystem.
Determining the 90% Effective Dose of Remimazolam Inhibiting Responses to Upper Gastrointestinal Endoscopy Insertion in Adults: A Double-Blind Study Utilizing a Biased Coin Up-and-Down Sequential Method
Authors: Yin Pengfei , Zhao Xian , Zhang Chaoliang , Shi Yi , Sheng Weiwei , Hu Binwei , Li Hui , Wang Mi , Kang Xianhui
Published: September 2023

Background. Remimazolam, a benzodiazepine sedative with clinical advantages, is used for anesthesia during GI endoscopy. However, the accurate clinical dosage remains understudied. This study aims to investigate the 90% effective dose (ED90) of remimazolam in inhibiting responses to upper GI endoscopy insertion and evaluate its efficacy and safety for upper GI endoscopic diagnosis and treatment. Methods. A total of 54 adult patients undergoing upper GI endoscopy under procedural sedation were included, and they were anesthetized with an intravenous bolus of remimazolam. The first patient was given a dose of 0.3 mg/kg of remimazolam and was next randomized according to a biased coin design (BCD) method, and each patient received a dose of remimazolam depending on the response of the previous patient. A positive reaction was defined as no choking cough, nausea and vomiting, and/or motor response during placement of the upper GI endoscope into pharyngeal cavity or within 3 minutes after placement; otherwise, it was a negative reaction. If positive, randomize the next patient’s dose of remimazolam to be unchanged or decrease by 0.05 mg/kg. If negative, increase the next patient’s dose of remimazolam by 0.05 mg/kg. According to the study protocol, at least 45 patients with positive reactions were needed to suspend the trial while monitoring anesthesia-related adverse events. Results. The ED90 of remimazolam for upper gastrointestinal endoscopy insertion was 0.556 mg/kg (95% CI: 0.399–0.578). All patients maintained stable circulation and no serious adverse events were observed during sedation. Patient satisfaction was 4.89 ± 0.69 points, anesthesiologist satisfaction was 4.57 ± 0.96 points, and endoscopist satisfaction was 4.67 ± 0.87 points (full score 5 points, minimum 1 point). Conclusion. The use of remimazolam for upper gastrointestinal endoscopy was safe and effective, with a single intravenous bolus at an ED90 dose of 0.556 mg/kg inhibiting responses to the procedure.
Genetic Evidence for a Potentially New Pathogenic Leptospira sp. Circulating in Bats from Brazilian Amazon
Authors: Di Azevedo Maria Isabel Nogueira , Verde Rair de Souza , Ezepha Camila , Carvalho-Costa Filipe Anibal , D’Andrea Paulo Sérgio , Medeiros Luciana dos Santos , Lilenbaum Walter
Published: September 2023

Leptospirosis is a neglected zoonosis frequently reported worldwide, caused by a spirochete of the genus Leptospira. It is capable of infecting domestic animals, free-living animals, and humans. Among wild animals, the role of bats in the epidemiology of leptospirosis has been investigated but is far from being elucidated. The Amazonian biome has the ideal conditions for maintaining and disseminating leptospires and, despite efforts that have been made to better understand leptospires’ occurrence in wild animals in the region, few studies aimed to explore and genetically characterize leptospires in bats. Based on this, the aim of the present study is to deeper investigate and genetically characterize leptospires detected in bats from the southwest Amazon. Animals were trapped by mist netting at five sites in the state of Acre, Brazil. Kidney samples were obtained and stored for molecular analysis. Polymerase chain reaction (PCR) was conducted first based on the LipL32 gene, and positive samples were submitted to rrs and secY-PCR and sequencing. Sequences were then submitted to phylogenetic analyses through multiple bioinformatic tools. The rrs sequences from the present study formed one single haplotype, different from any other previously deposited, grouped in a highly supported cluster with sequences from bats from Madagascar and China. The initial secY screening revealed no identity with previously deposited sequences. The phylogenetic trees revealed the sequences from the present study in an isolated branch, clearly separated from all previously known pathogenic Leptospira spp., suggesting the existence of a potentially undescribed species. The haplotype network including only leptospires from the Amazon region confirmed two new haplotypes from the same taxon unity, isolated from the others, with a probable origin of the species from L. noguchii. The characterization of this potentially new species in bats reinforces the complexity of the transmission dynamics of leptospires, including wild, periurban, and urban environments, emphasizing the need for an integrative look at leptospirosis vigilance within the context of One Health.
Exercise Training Reduces the Inflammatory Response and Promotes Intestinal Mucosa-Associated Immunity in Lynch Syndrome
Authors: Deng Nan , Reyes-Uribe Laura , Fahrmann Johannes F. , Thoman Whittney S. , Munsell Mark F. , Dennison Jennifer B. , Murage Eunice , Wu Ranran , Hawk Ernest T. , Thirumurthi Selvi , Lynch Patrick M. , Dieli-Conwright Christina M. , Lazar Alexander J. , Jindal Sonali , Chu Khoi , Chelvanambi Manoj , Basen-Engquist Karen , Li Yisheng , Wargo Jennifer A. , McAllister Florencia , Allison James P. , Sharma Padmanee , Sinha Krishna M. , Hanash Samir , Gilchrist Susan C. , Vilar Eduardo
Published: September 2023

Purpose:

Lynch syndrome (LS) is a hereditary condition with a high lifetime risk of colorectal and endometrial cancers. Exercise is a non-pharmacologic intervention to reduce cancer risk, though its impact on patients with LS has not been prospectively studied. Here, we evaluated the impact of a 12-month aerobic exercise cycling intervention in the biology of the immune system in LS carriers.

Patients and Methods:

To address this, we enrolled 21 patients with LS onto a non-randomized, sequential intervention assignation, clinical trial to assess the effect of a 12-month exercise program that included cycling classes 3 times weekly for 45 minutes versus usual care with a one-time exercise counseling session as control. We analyzed the effects of exercise on cardiorespiratory fitness, circulating, and colorectal-tissue biomarkers using metabolomics, gene expression by bulk mRNA sequencing, and spatial transcriptomics by NanoString GeoMx.

Results:

We observed a significant increase in oxygen consumption (VO2peak) as a primary outcome of the exercise and a decrease in inflammatory markers (prostaglandin E) in colon and blood as the secondary outcomes in the exercise versus usual care group. Gene expression profiling and spatial transcriptomics on available colon biopsies revealed an increase in the colonic mucosa levels of natural killer and CD8+ T cells in the exercise group that were further confirmed by IHC studies.

Conclusions:

Together these data have important implications for cancer interception in LS, and document for the first-time biological effects of exercise in the immune system of a target organ in patients at-risk for cancer.
Entinostat Enhances the Efficacy of Chemotherapy in Small Cell Lung Cancer Through S-phase Arrest and Decreased Base Excision Repair
Authors: Solta Anna , Boettiger Kristiina , Kovács Ildikó , Lang Christian , Megyesfalvi Zsolt , Ferk Franziska , Mišík Miroslav , Hoetzenecker Konrad , Aigner Clemens , Kowol Christian R. , Knasmueller Siegfried , Grusch Michael , Szeitz Beáta , Rezeli Melinda , Dome Balazs , Schelch Karin
Published: September 2023

Purpose:

Acquired chemoresistance is a frequent event in small cell lung cancer (SCLC), one of the deadliest human malignancies. Histone deacetylase inhibitors (HDACi) have been shown to synergize with different chemotherapeutic agents including cisplatin. Accordingly, we aimed to investigate the dual targeting of HDAC inhibition and chemotherapy in SCLC.

Experimental Design:

The efficacy of HDACi and chemotherapy in SCLC was investigated both in vitro and in vivo. Synergistic drug interactions were calculated based on the HSA model (Combenefit software). Results from the proteomic analysis were confirmed via ICP-MS, cell-cycle analysis, and comet assays.

Results:

Single entinostat- or chemotherapy significantly reduced cell viability in human neuroendocrine SCLC cells. The combination of entinostat with either cisplatin, carboplatin, irinotecan, epirubicin, or etoposide led to strong synergy in a subset of resistant SCLC cells. Combination treatment with entinostat and cisplatin significantly decreased tumor growth in vivo. Proteomic analysis comparing the groups of SCLC cell lines with synergistic and additive response patterns indicated alterations in cell-cycle regulation and DNA damage repair. Cell-cycle analysis revealed that cells exhibiting synergistic drug responses displayed a shift from G1 to S-phase compared with cells showing additive features upon dual treatment. Comet assays demonstrated more DNA damage and decreased base excision repair in SCLC cells more responsive to combination therapy.

Conclusions:

In this study, we decipher the molecular processes behind synergistic interactions between chemotherapy and HDAC inhibition. Moreover, we report novel mechanisms to overcome drug resistance in SCLC, which may be relevant to increasing therapeutic success.
Targeting DNA Repair and Survival Signaling in Diffuse Intrinsic Pontine Gliomas to Prevent Tumor Recurrence
Authors: Sharma Monika , Barravecchia Ivana , Teis Robert , Cruz Jeanette , Mumby Rachel , Ziemke Elizabeth K. , Espinoza Carlos E. , Krishnamoorthy Varunkumar , Magnuson Brian , Ljungman Mats , Koschmann Carl , Chandra Joya , Whitehead Christopher E. , Sebolt-Leopold Judith S. , Galban Stefanie
Published: September 2023

Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood–brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Because radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of Ataxia Telangiectasia Mutated to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG.

Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.
Supplemental Table 1 from AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol
Authors: Detlefsen Andrea J. , Mesaros Clementina A. , Duan Ling , Penning Trevor M.
Published: September 2023

Structures of AKR1C3 Inhibitors
Supplemental Figure 3 from AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol
Authors: Detlefsen Andrea J. , Mesaros Clementina A. , Duan Ling , Penning Trevor M.
Published: September 2023

Supplemental Figure 3 shows DHEA-S to T metabolism in AKR1C3 KD cell lines as measured by SID-LC-MS/MS.
Supplemental Figure 2 from AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol
Authors: Detlefsen Andrea J. , Mesaros Clementina A. , Duan Ling , Penning Trevor M.
Published: September 2023

Supplemental Figure 2 shows standard curves generated for hydroxyandrogens using SIC-LC-MS/MS.
Supplemental Figure 1 from AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol
Authors: Detlefsen Andrea J. , Mesaros Clementina A. , Duan Ling , Penning Trevor M.
Published: September 2023

Supplemental Figure 1 shows the picolinic acid derivatization scheme and SIC-LC-MSMS chromatographic separation of picolinic acid derivatized hydroxyandrogens.
FIGURE 4 from AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol
Authors: Detlefsen Andrea J. , Mesaros Clementina A. , Duan Ling , Penning Trevor M.
Published: September 2023

DHEA-S stimulated cell growth. Cell growth from castrate (5 µmol/L) DHEA-S (A) and post-Abi (0.5 µmol/L) DHEA-S (B) in CWR22PC WT cells ± ASP-9521 or BMT4-159 and in CWR22PC AKR1C3 KD cells. Cell growth from castrate (5 µmol/L) DHEA-S (C) and post-Abi (0.5 µmol/L) DHEA-S (D) in DuCaP WT cells ± ASP-9521 or BMT4-159 and in DuCaP AKR1C3 KD cells. P values indicated where ***, P < 0.0001; **, P < 0.001; and *, P < 0.01 compared with growth of WT cells treated with DHEA-S at the 10-day timepoint. Statistical significance was determined by a one-way ANOVA.
FIGURE 2 from AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol
Authors: Detlefsen Andrea J. , Mesaros Clementina A. , Duan Ling , Penning Trevor M.
Published: September 2023

AKR1C3 expression in WT versus KD cell lines. qRT-PCR shows fg transcript/fg GAPDH for CWR22PC WT and AKR1C3 KD cells (A), and DuCaP WT and AKR1C3 KD cells (B). AKR1C3 protein expression for CWR22PC WT versus AKR1C3 KD and DuCaP WT versus AKR1C3 KD with α-Tubulin loading control (C). P values represented by *** is P < 0.0001. AKR1C3 expression is compared between WT and AKR1C3 KD cell lines using one-way ANOVA. Expression of other 17-oxidoreductase enzymes are compared with AKR1C3 expression within respective cell lines (WT or 1C3 KD) using a one-way ANOVA.
Data from AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol
Authors: Detlefsen Andrea J. , Mesaros Clementina A. , Duan Ling , Penning Trevor M.
Published: September 2023

Androgen receptor signaling inhibitors (ARSI) are used to treat castration-resistant prostate cancer (CRPC) to stop a resurgence of androgen receptor (AR) signaling. Despite early success, patients on ARSIs eventually relapse, develop drug resistance, and succumb to the disease. Resistance may occur through intratumoral steroidogenesis mediated by upregulation of aldo-keto reductase family 1C member 3 (AKR1C3). Patients treated with leuprolide (castrate) and those treated with leuprolide plus abiraterone (post-Abi) harbor a reservoir of DHEA-S which could fuel testosterone (T) biosynthesis via AKR1C3 to cause a resurgence of prostate cancer cell growth. We demonstrate that concentrations of DHEA-S found in castrate and post-Abi patients are (i) converted to T in an AKR1C3-dependent manner in prostate cancer cells, and (ii) in amounts sufficient to stimulate AKR1C3-dependent cell growth. We observed this in primary and metastatic prostate cancer cell lines, CWR22PC and DuCaP, respectively. Androgen measurements were made by stable isotope dilution LC-MS/MS. We demonstrate AKR1C3 dependence using stable short hairpin RNA knockdown and pharmacologic inhibitors. We also demonstrate that free DHEA is reduced to 5-androstene-3β,17β-diol (5-Adiol) by AKR1C3 and that this is a major metabolite, suggesting that in our cell lines 5-Adiol is a predominant precursor of T. We have identified a mechanism of ARSI resistance common to both primary and metastatic cell lines that is dependent on the conversion of DHEA to 5-Adiol on route to T catalyzed by AKR1C3.
Significance:
We show that reservoirs of DHEA-S that remain after ARSI treatment are converted into T in primary and metastatic prostate cancer cells in amounts sufficient to stimulate cell growth. Pharmacologic and genetic approaches demonstrate that AKR1C3 is required for these effects. Furthermore, the route to T proceeds through 5-Adiol. We propose that this is a mechanism of ARSI drug resistance.
Development of an Oral Immunotherapy-Related Parental Burden Scale
Authors: Maeta Akihiro , Takaoka Yuri , Hamada Masaaki , Nakano Atsuko , Sumimoto Shinichi , Anzai Kaori , Tanaka Yukiko , Morikawa Satoru , Kameda Makoto , Takahashi Kyoko
Published: September 2023

Introduction: Oral immunotherapy (OIT) imposes a burden on parents and their children with food allergies (FAs). We already developed a questionnaire for OIT-related Parental Burden (OIT-PB) scale. However, the previous questionnaire had some problems. This study modified OIT-PB and verified its reliability and validity. Methods: A 20-item draft covering the physical and mental burdens caused by OIT was prepared jointly with multiple allergists. The Food Allergy Quality of Life Questionnaire-Parental Burden (FAQLQ-PB) and Stress Response Scale-18 (SRS-18) were used to verify concurrent validity. A questionnaire survey was administered during treatment to parents of FA children who had started OIT for the first time. An additional OIT-PB survey was performed at one specific institution 1 week after the posttreatment survey. Results: The responses of 64 of the 76 recruited parents were analyzed. Of the 20 questions, 1 item was excluded owing to the floor effect, 1 was excluded because its commonality was less than 0.2, and 2 were excluded because their factor loading values were less than 0.4. Factor analysis was used to classify the OIT-PB into the following 4 subscales: “burden caused by adherence to treatment plan,” “anxiety about symptom-induced risk,” “burden due to patient’s eating behavior,” and “anxiety about treatment effect.” The Cronbach’s α for all 16 items of the OIT-PB was 0.893; Cronbach’s α for each subscale was 0.876, 0.898, 0.874, and 0.717. The re-test reliability coefficient was 0.864 (95% confidence interval [CI]: 0.720−0.937, p < 0.001). A significant positive correlation was found between the OIT-PB and FAQLQ-PB (R = 0.610 [95% CI: 0.422−0.747], p < 0.001) and the SRS-18 (R = 0.522 [95% CI: 0.306–0.687], p < 0.001). A significant negative correlation was found between the rate of increase in OIT food intake and the “anxiety about treatment effect” score (R = −0.355 [95% CI: −0.558–0.112], p < 0.001). Parents of children on the hen’s egg OIT treatment scored higher on the “burden due to patient’s eating behavior” subscale than did parents of children on the milk and wheat OIT treatment. Conclusion: The burden of OIT experienced by parents can be broadly classified into four categories. The modified OIT-PB was able to evaluate them individually and was shown to have reliability and validity. This scale is expected to be useful in the development of OIT that considers not only therapeutic effect but also the burden experienced by FA children and their parents.
Effectiveness of Immediate Video-Assisted Thoracoscopic Surgery for Empyema: A Multicentre, Retrospective Cohort Study
Authors: Shiroshita Akihiro , Kimura Yuya , Yamada Atsushi , Shirakawa Chigusa , Yue Cong , Suzuki Hokuto , Anan Keisuke , Sato Kenya , Nakashima Kiyoshi , Takeshita Masafumi , Okuno Takehiro , Nitawaki Tatsuya , Igei Hiroshi , Suzuki Jun , Tomii Keisuke , Ohgiya Masahiro , Kataoka Yuki
Published: September 2023

Background: Because of limitations in previous randomised controlled trials and observational studies, the effectiveness of immediate video-assisted thoracoscopic surgery (VATS) for patients with empyema in real-world settings remains unclear. Objective: This study aimed to evaluate whether immediate VATS improves clinical outcomes in patients with empyema. Methods: This multicentre retrospective cohort study included 744 patients with physician-diagnosed empyema from six hospitals between 2006 and 2021. The exposure was VATS performed within 3 days of empyema diagnosis, the primary outcome was 30-day mortality, and secondary outcomes were 90-day mortality, length of hospital stay, and time from diagnosis to discharge. We used propensity score weighting to account for potential confounders. For outcome analyses, we used logistic regression for mortality outcomes and gamma regression for the number of days. Results: Among the 744 patients, 53 (7.1%) underwent VATS within 3 days, and 691 (92.9%) initially received conservative treatment. After propensity score weighting, the differences in 30- and 90-day mortalities between the immediate VATS and initial conservative treatment groups were 1.18% (95% confidence interval [CI], −10.7 to 13.0%) and −0.08% (95% CI, −10.3 to 10.2%), respectively. The differences in length of hospital stay and time from diagnosis to discharge were −3.22 (95% CI, −6.19 to −0.25 days) and −5.04 days (95% CI, −8.19 to −1.90 days), respectively. Conclusions: Our real-world study showed that immediate VATS reduced the length of hospital stay and the time from diagnosis to discharge. Considering the small sample and differences in protocols between countries, further large-scale studies are warranted.
From Early Motor Ability to Global Cognitive Development 7 Years after Neonatal Arterial Ischemic Stroke
Authors: Giraud Antoine , Garel Pauline , Walsh Brian H. , Chabrier Stéphane
Published: September 2023

The developmental condition of children after neonatal arterial ischemic stroke (NAIS) is characterized by cognitive and motor impairments. We hypothesized that independent walking age would be a predictor of later global cognitive functioning in this population. Sixty-one children with an available independent walking age and full-scale intelligence quotient (IQ) score 7 years after NAIS were included in this study. Full-scale IQ was assessed using the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV). Independent walking age was negatively correlated with full-scale IQ score at 7 years of age (Pearson correlation coefficient of −0.27; 95% confidence interval from −0.48 to −0.01; p < 0.05). Early motor function is correlated with later global cognitive functioning in children after NAIS. Assessing and promoting early motor ability is essential in this population.
The Clinical Relevance of the Lingual Branch in Ridge Augmentation of the Posterior Mandible: A Pilot Cadaver Study
Authors: Shahbazi Arvin , Windisch Péter , Tubbs R. Shane , Decater Tess , Urbán István A. , Baksa Gábor , Iwanaga Joe
Published: September 2023

Guided bone regeneration (GBR) requires a tension-free flap without damaging the collateral circulation in order to secure better surgical outcomes. Topographic knowledge regarding the neurovascular bundles in the posterior aspect of the mandible can prevent complications during lingual flap design. The lingual branch (LB) of the inferior alveolar or maxillary arteries is not sufficiently illustrated or described in the literature. Nevertheless, it has an intimate relationship with the lingual nerve (LN) during ridge augmentation and implant-related posterior mandible surgery. Therefore, this study aimed to clarify the morphology and topography of the LB related to GBR surgeries. In the present human cadaveric study, the LB was analyzed in 12 hemimandibles using latex injection and corrosion casting. Two types of LB were identified based on their origin and course. The LB was found in a common connective tissue sheath close to the LN. The LB assembled several anastomoses on the posterior lingual aspect of the mandible and retromolar area. The LB acted as an anatomical landmark in identifying LN at the posterior lingual aspect of the mandible.
Cardiovascular Molecular Imaging With Fluorine-19 MRI: The Road to the Clinic
Authors: van Heeswijk Ruud B. , Bauer Wolfgang R. , Bönner Florian , Janjic Jelena M. , Mulder Willem J.M. , Schreiber Laura M. , Schwitter Juerg , Flögel Ulrich
Published: September 2023

Fluorine-19 (
19
F) magnetic resonance imaging is a unique quantitative molecular imaging modality that makes use of an injectable fluorine-containing tracer that generates the only visible
19
F signal in the body. This hot spot imaging technique has recently been used to characterize a wide array of cardiovascular diseases and seen a broad range of technical improvements. Concurrently, its potential to be translated to the clinical setting is being explored. This review provides an overview of this emerging field and demonstrates its diagnostic potential, which shows promise for clinical translation. We will describe
19
F magnetic resonance imaging hardware, pulse sequences, and tracers, followed by an overview of cardiovascular applications. Finally, the challenges on the road to clinical translation are discussed.
Comparison of CT-derived Plaque Characteristic Index With CMR Perfusion for Ischemia Diagnosis in Stable CAD
Authors: Guo Wei-feng , Xu Hai-jia , Lu Yi-ge , Qiao Guan-yu , Yang Shan , Zhao Shi-hai , Jin Hang , Dai Neng , Yao Zhi-feng , Yin Jia-sheng , Li Chen-guang , He Wei , Zeng Mengsu
Published: September 2023

BACKGROUND:

Coronary computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR) have been used to diagnose lesion-specific ischemia in patients with coronary artery disease. The aim of this study was to investigate the diagnostic performance of CCTA-derived plaque characteristic index compared with myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) derived from CMR perfusion in the assessment of lesion-specific ischemia.

METHODS:

Between October 2020 and March 2022, consecutive patients with suspected or known coronary artery disease, who were clinically referred for invasive coronary angiography were prospectively enrolled. All participants sequentially underwent CCTA and CMR and invasive fractional flow reserve within 2 weeks. The diagnostic performance of CCTA-derived plaque characteristics, CMR perfusion-derived stress MBF, and MPR were compared. Lesions with fractional flow reserve ≤0.80 were considered to be hemodynamically significant stenosis.

RESULTS:

Nighty-two patients with 141 vessels were included in this study. Plaque length, minimum luminal area, plaque area, percent area stenosis, total atheroma volume, vessel volume, lipid-rich volume, spotty calcium, napkin-ring signs, stress MBF, and MPR in flow-limiting stenosis group were significantly different from nonflow-limiting group. The overall accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of lesion-specific ischemia diagnosis were 61.0%, 55.3%, 63.1%, 35.6%, and 79.3% for stress MBF, and 89.4%, 89.5%, 89.3%, 75.6%, 95.8% for MPR; meanwhile, 82.3%, 79.0%, 84.5%, 65.2%, and 91.6% for CCTA-derived plaque characteristic index.

CONCLUSIONS:

In our prospective study, CCTA-derived plaque characteristics and MPR derived from CMR performed well in diagnosing lesion-specific myocardial ischemia and were significantly better than stress MBF in stable coronary artery disease.
Psychosocial Stressors at Work and Coronary Heart Disease Risk in Men and Women: 18-Year Prospective Cohort Study of Combined Exposures
Authors: Lavigne-Robichaud Mathilde , Trudel Xavier , Talbot Denis , Milot Alain , Gilbert-Ouimet Mahée , Vézina Michel , Laurin Danielle , Dionne Clermont E. , Pearce Neil , Dagenais Gilles R. , Brisson Chantal
Published: September 2023

BACKGROUND.

Psychosocial stressors at work, like job strain and effort-reward imbalance (ERI), can increase coronary heart disease (CHD) risk. ERI indicates an imbalance between the effort and received rewards. Evidence about the adverse effect of combined exposure to these work stressors on CHD risk is scarce. This study examines the separate and combined effect of job strain and ERI exposure on CHD incidence in a prospective cohort of white-collar workers in Quebec, Canada.

METHODS.

Six thousand four hundred sixty-five white-collar workers without cardiovascular disease (mean age, 45.3±6.7) were followed for 18 years (from 2000 to 2018). Job strain and ERI were measured with validated questionnaires. CHD events were retrieved from medico-administrative databases using validated algorithms. Marginal Cox models were used to calculate hazard ratios (HR) stratified by sex. Multiple imputation and inverse probability weights were applied to minimize potential threats to internal validity.

RESULTS.

Among 3118 men, 571 had a first CHD event. Exposure to either job strain or ERI was associated with an adjusted 49% CHD risk increase (HR, 1.49 [95% CI, 1.07–2.09]). Combined exposure to job strain and ERI was associated with an adjusted 103% CHD risk increase (HR, 2.03 [95% CI, 1.38–2.97]). Exclusion of early CHD cases and censoring at retirement did not alter these associations. Among 3347 women, 265 had a first CHD event. Findings were inconclusive (passive job HR, 1.24 [95% CI, 0.80–1.91]; active job HR, 1.16 [95% CI, 0.70–1.94]; job strain HR, 1.08 [95% CI, 0.66–1.77]; ERI HR, 1.02 [95% CI, 0.72–1.45]).

CONCLUSIONS.

In this prospective cohort study, men exposed to job strain or ERI, separately and in combination, were at increased risk of CHD. Early interventions on these psychosocial stressors at work in men may be effective prevention strategies to reduce CHD burden. Among women, further investigation is required.
Winning the Lottery With Neural Connectivity Constraints: Faster Learning Across Cognitive Tasks With Spatially Constrained Sparse RNNs
Authors: Khona Mikail , Chandra Sarthak , Ma Joy J. , Fiete Ila R.
Published: September 2023

Recurrent neural networks (RNNs) are often used to model circuits in the brain and can solve a variety of difficult computational problems requiring memory, error correction, or selection (Hopfield, 1982; Maass et al., 2002; Maass, 2011). However, fully connected RNNs contrast structurally with their biological counterparts, which are extremely sparse (about 0.1%). Motivated by the neocortex, where neural connectivity is constrained by physical distance along cortical sheets and other synaptic wiring costs, we introduce locality masked RNNs (LM-RNNs) that use task-agnostic predetermined graphs with sparsity as low as 4%. We study LM-RNNs in a multitask learning setting relevant to cognitive systems neuroscience with a commonly used set of tasks, 20-Cog-tasks (Yang et al., 2019). We show through reductio ad absurdum that 20-Cog-tasks can be solved by a small pool of separated autapses that we can mechanistically analyze and understand. Thus, these tasks fall short of the goal of inducing complex recurrent dynamics and modular structure in RNNs. We next contribute a new cognitive multitask battery, Mod-Cog, consisting of up to 132 tasks that expands by about seven-fold the number of tasks and task complexity of 20-Cog-tasks. Importantly, while autapses can solve the simple 20-Cog-tasks, the expanded task set requires richer neural architectures and continuous attractor dynamics. On these tasks, we show that LM-RNNs with an optimal sparsity result in faster training and better data efficiency than fully connected networks.