bluuebunny/crossref_metadata_2025 huggingface dataset:
Supporting evidence in phase 2 cancer trial protocols: a content analysis
Authors: Bicer Selin , Nelson Angela , Carayannis Katerina , Kimmelman Jonathan
Published: November 2024

Background

Phase 2 trials are instrumental for designing definitive efficacy trials or attaining accelerated approval. However, high attrition of drug candidates in phase 2 trials raises questions about their supporting evidence.

Methods

We developed a typology of supporting evidence for phase 2 cancer trials. We also devised a scheme for capturing elements that enable an assessment of the strength of such evidence. Using this framework, we content analyzed supporting evidence provided in protocols of 50 randomly sampled phase 2 cancer monotherapy trials between January 2014 and January 2019, available on ClinicalTrials.gov.

Results

Of the 50 protocols in our sample, 52% were industry funded. Most invoked supporting evidence deriving from trials against different cancers (n = 28, 56%) or preclinical studies (n = 48, 96%) but not from clinical studies involving the target drug-indication pairing (n = 23, 46%). When presenting evidence from models, only 1 (2%) protocol explained its translational relevance. Instead, protocols implied translatability by describing molecular (86%) and pathophysiological (84%) processes shared by model and target systems. Protocols often provided information for assessing the magnitude, precision, and risk of bias for supporting trials (n = 43; 93%, 91%, 47%, respectively). However, such information was often unavailable for preclinical studies (n = 49; 53%, 22%, 59%, respectively).

Conclusions

Supporting evidence is key to justifying the commitment of scientific resources and patients to a clinical hypothesis. Protocols often omit elements that would enable critical assessment of supporting evidence for phase 2 monotherapy cancer trials. These gaps suggest the promise of more structured approaches for presenting supporting evidence.
Human papillomavirus prophylactic vaccines: update on new vaccine development and implications for single-dose policy
Authors: Schuind Anne E , Balaji Kanduri Ananth , Du Anna , Yuan Yuan , Dull Peter
Published: November 2024

Human papillomavirus (HPV) prophylactic vaccines were first licensed in 2006 with the primary goal of preventing HPV-related cancers, with cervical cancer accounting for the highest morbidity and mortality globally. Six HPV vaccines have been licensed; 4 of these have been prequalified by the World Health Organization, and additional products are in the pipeline. This article provides an overview of HPV vaccine coverage and current and anticipated vaccine supply vs expected demand. Given that the 2022 World Health Organization position paper on HPV vaccines includes a 1-dose regimen as an alternate schedule, we will discuss the evidence for using licensed vaccines in single-dose regimens and the approach to generating similar supportive data for other current and future vaccines. The broad adoption of a single-dose HPV vaccine regimen would expand access to vaccines by improving the supply-demand balance, increasing affordability, and simplifying logistics, which will ultimately impact HPV-related morbidity and mortality.
Leveraging single-dose human papillomavirus vaccination dose-efficiency to attain cervical cancer elimination in resource-constrained settings
Authors: Man Irene , Georges Damien , Basu Partha , Baussano Iacopo
Published: November 2024

Background

In low- and middle-income countries, resource constraints remain a critical factor limiting access to cervical cancer preventive measures. The option of single-dose immunization could help improve access to human papillomavirus vaccination and attain cervical cancer elimination.

Methods

With simulation models adapted to country-specific data and scenarios for single-dose protection derived from International Agency for Research on Cancer India vaccine trial data, we estimated the expected impact of single-dose vaccination in India, Rwanda, and Brazil, three countries with varying profiles of cervical cancer risk and vaccination timelines. In combination with single-dose vaccination, we explored different resource reallocation strategies based on dose efficiency, elimination attainment, and cervical cancer cases prevented, with the existing 2-dose program as a comparator.

Results

Assuming lifelong single-dose protection, switching from 2-dose to 1-dose vaccination and reallocating resources to female catch-up could prevent 467-1336, 94-194, and 15-207 additional cervical cancer cases (per 100 000 women born) in cohorts aged 11-30 years in India, Rwanda, and Brazil, respectively. Resource reallocation to improve the current routine coverage could help eliminate cervical cancer in India and across all Brazilian states but not in Rwanda. For each country, we found a dose-efficient reallocation strategy (or a combination of strategies) together with 1-dose vaccination that could prevent more cervical cancers vs 2-dose vaccination, even in the worst-case scenario of single-dose protection.

Conclusion

Adopting single-dose vaccination with resource reallocation is a resource-efficient approach to enhance progress toward cervical cancer elimination. The overall impact of vaccination can be maximized by fine-tuning resource reallocation to a country’s needs.
Population-level health impact of hypothetical waning 1-dose human papillomavirus vaccination and 2-dose mitigation strategies in a high cervical cancer burden setting
Authors: Burger Emily A , Laprise Jean-François , Portnoy Allison , Spencer Jennifer C , Sy Stephen , Regan Mary Caroline , Bénard Élodie , Drolet Mélanie , Brisson Marc , Kim Jane J
Published: November 2024

Background

We simulated the impact of hypothetical waning scenarios of a 1-dose human papillomavirus (HPV) vaccination paired with switching to 2-dose mitigation strategies guided by empirical vaccine trial reporting timelines.

Methods

Using 2 independent mathematical models fitted to a high-burden setting, we projected the cumulative cervical cancer cases averted over 85 years for alternative HPV vaccination scenarios under 2 program adoption timelines: 1) de novo introduction of a 1-dose HPV vaccination and 2) a switch from an existing 2-dose HPV vaccination program to a 1-dose vaccination. We assumed 80% vaccination coverage with the bivalent vaccine and an average duration of a 1-dose HPV vaccine protection of either 30 or 25 years with 100% efficacy. We varied the eligible age group(s) at program introduction and the 2-dose mitigation (single-age cohort or multi-age cohort). If needed for mitigation, reintroduction of 2-dose vaccination was assumed to occur in 2036 (ie, 30 years after initiation of the Costa Rica Vaccine Trial).

Results

Under both vaccine adoption timelines, the models projected that countries could achieve the same level of health benefits by switching to 2 doses in 2036 using a multi-age cohort approach as with initiating a 2-dose or 1-dose vaccination program with no waning. With only a single-age cohort 2-dose mitigation approach, 98%-99% of cases would be prevented compared with the health benefits of 2 doses or a noninferior, durable 1 dose.

Conclusions

Countries hesitant to adopt a 1-dose HPV vaccination program may have opportunities to leverage the benefits and efficiency of a 1-dose schedule while awaiting longer-term reporting from 1-dose durability studies, including Costa Rica Vaccine Trial.
Impact of single-dose HPV vaccination on HPV 16 and 18 prevalence in South African adolescent girls with and without HIV
Authors: Delany-Moretlwe Sinead , Machalek Dorothy A , Travill Danielle , Petoumenos Kathy , Nyemba Dorothy C , Mbulawa Zizipho Z A , Ndlovu Nontokozo , Kaldor John M , Rees Helen
Published: November 2024

Background

The World Health Organization has endorsed single-dose human papillomavirus (HPV) vaccination, but data on the impact on HPV prevalence in high HIV burden settings are limited.

Methods

A single-dose bivalent HPV vaccine was delivered to adolescent girls in grade 10 in a schools-based campaign in 1 district in South Africa. Impact on HPV 16 and 18 prevalence was evaluated using repeat cross-sectional surveys. A clinic-based survey in girls aged 17-18 years established HPV 16 and 18 prevalence in a prevaccine population (n = 506, including 157 living with HIV) in 2019 and was repeated in the same age group and sites in a single-dose eligible population in 2021 (n = 892, including 117 with HIV). HPV DNA was detected on self-collected vaginal swabs using the Seegene Anyplex II HPV 28. Population impact was estimated overall and by HIV status using prevalence ratios adjusted for differences in sexual behavior between surveys.

Results

Single-dose vaccination campaign coverage was 72% (4807 of 6673) of eligible girls attending high school (n = 66) in the district. HPV 16 and 18 prevalence was 35% lower in the postvaccine survey overall (adjusted prevalence ratio = 0.65, 95% confidence interval [CI] = 0.51 to 0.83; P < .001) and 37% lower in those living with HIV (adjusted prevalence ratio = 0.63, 95% CI = 0.41 to 0.95; P  = .026). No protective effect was seen for nonvaccine oncogenic HPV types 33, 35, 39, 51, 52, 56, 58, 59, or 68 overall (adjusted prevalence ratio = 1.14, 95% CI = 1.03 to 1.26; P = .011) or in those living with HIV (adjusted prevalence ratio = 1.00, 95% CI = 0.83 to 1.21. P = 0.99).

Conclusion

These data provide reassuring evidence of single-dose impact on population-level HPV 16 and 18 prevalence in a South African population, irrespective of HIV status.
Post-criticality and the pursuit of an empirical philosophy of education: epistemology, methodology, ethics
Authors: Schildermans Hans , Vlieghe Joris , Wortmann Kai
Published: November 2024

This article examines the relevance of post-criticality as a research stance across various traditions in educational research. After problematizing the dominance of critical approaches centred on deconstruction and denunciation, the authors advocate instead for an empirical philosophy of education. This article sets the stage for a suite of articles, published in this issue, which explore affirmative, engaged methodologies that prioritize proximity to educational practices over detached critique. Collectively, the articles investigate how post-critical methodologies can produce richer understandings of educational realities and foster meaningful connections between theory and practice.
α-separability and adjustable combination of amplitude and phase model for functional data
Authors: Wang Tian , Ding Jimin
Published: November 2024

We consider separating and joint modelling amplitude and phase variations for functional data in an identifiable manner. To rigorously address this separability issue, we introduce the notion of α-separability upon constructing a family of α-indexed metrics. We bridge α-separability with the uniqueness of Fréchet mean, leading to the proposed adjustable combination of amplitude and phase model. The parameter α allows user-defined modelling emphasis between vertical and horizontal features and provides a novel viewpoint on the identifiability issue. We prove the consistency of the sample Fréchet mean and variance, and the proposed estimators. Our method is illustrated in simulations and COVID-19 infection rate data.
Splenic artery pseudoaneurysm rupture post-laparoscopic sleeve gastrectomy
Authors: Babic Stephanie M , Ramachandran Roshan N
Published: November 2024

A splenic artery pseudoaneurysm (SAP) is a rare vascular entity that is becoming increasingly recognized as a potential complication of bariatric surgery. This is a case of a 36-year-old woman brought by ambulance to a regional emergency department with abdominal pain, collapse, and gross haemodynamic instability 2 years post-laparoscopic sleeve gastrectomy. She received aggressive resuscitation in the emergency department but could not be stabilized and so underwent an emergency laparotomy. Intra-operatively, she was found to have a ruptured SAP with active bleeding, which was managed with a splenectomy. A high index of suspicion is required in any patient presenting with abdominal pain and circulatory collapse in the context of previous bariatric surgery. In rural or regional settings without immediate access to interventional radiology services, the most appropriate management option will almost invariably be an emergency laparotomy and splenectomy due to the risk of deterioration during patient transfer.
Comparative Genomics Provides Insights into Adaptive Evolution and Demographics of Bats
Authors: Liu Gaoming , Pan Qi , Zhu Pingfen , Guo Xinyu , Zhang Zhan , Li Zihao , Zhang Yaolei , Zhang Xiaoxiao , Wang Jiahao , Liu Weiqiang , Hu Chunyan , Yu Yang , Wang Xiao , Chen Weixiao , Li Meng , Yu Wenhua , Liu Xin , Seim Inge , Fan Guangyi , Zhou Xuming
Published: November 2024

Bats possess a range of distinctive characteristics, including flight, echolocation, impressive longevity, and the ability to harbor various zoonotic pathogens. Additionally, they account for the second-highest species diversity among mammalian orders, yet their phylogenetic relationships and demographic history remain underexplored. Here, we generated de novo assembled genomes for 17 bat species and 2 of their mammalian relatives (the Amur hedgehog and Chinese mole shrew), with 12 genomes reaching chromosome-level assembly. Comparative genomics and ChIP-seq assays identified newly gained genomic regions in bats potentially linked to the regulation of gene activity and expression. Notably, some antiviral infection-related gene under positive selection exhibited the activity of suppressing cancer, evidencing the linkage between virus tolerance and cancer resistance in bats. By integrating published bat genome assemblies, phylogenetic reconstruction established the proximity of noctilionoid bats to vesper bats. Interestingly, we found 2 distinct patterns of ancient population dynamics in bats and population changes since the last glacial maximum does not reflect species phylogenetic relationships. These findings enriched our understanding of adaptive mechanisms and demographic history of bats.
The evolution of dbSNP: 25 years of impact in genomic research
Authors: Phan Lon , Zhang Hua , Wang Qiang , Villamarin Ricardo , Hefferon Tim , Ramanathan Aravinthan , Kattman Brandi
Published: November 2024

The Single Nucleotide Polymorphism Database (dbSNP), established in 1998 by the National Center for Biotechnology Information (NCBI), has been a critical resource in genomics for cataloging small genetic variations. Originally focused on single nucleotide polymorphisms (SNPs), dbSNP has since expanded to include a variety of genetic variants, playing a key role in genome-wide association studies (GWAS), population genetics, pharmacogenomics, and cancer research. Over 25 years, dbSNP has grown to include more than 4.4 billion submitted SNPs and 1.1 billion unique reference SNPs, providing essential data for identifying disease-related genetic variants and studying human diversity. Integrating large-scale projects like 1000 Genomes, gnomAD, TOPMed, and ALFA has expanded dbSNP’s catalog of human genetic variation, increasing its usefulness for research and clinical applications. Keeping up with advancements such as next-generation sequencing and cloud-based infrastructure, dbSNP remains a cornerstone of genetic research supporting continued discoveries in precision medicine and population genomics. DATABASE URL: https://www.ncbi.nlm.nih.gov/snp.
Overcoming nucleotide bias in the nonenzymatic copying of RNA templates
Authors: Duzdevich Daniel , Carr Christopher E , Colville Ben W F , Aitken Harry R M , Szostak Jack W
Published: November 2024

The RNA World hypothesis posits that RNA was the molecule of both heredity and function during the emergence of life. This hypothesis implies that RNA templates can be copied, and ultimately replicated, without the catalytic aid of evolved enzymes. A major problem with nonenzymatic template-directed polymerization has been the very poor copying of sequences containing rA and rU. Here, we overcome that problem by using a prebiotically plausible mixture of RNA mononucleotides and random-sequence oligonucleotides, all activated by methyl isocyanide chemistry, that direct the uniform copying of arbitrary-sequence templates, including those harboring rA and rU. We further show that the use of this mixture in copying reactions suppresses copying errors while also generating a more uniform distribution of mismatches than observed for simpler systems. We find that oligonucleotide competition for template binding sites, oligonucleotide ligation and the template binding properties of reactant intermediates work together to reduce product sequence bias and errors. Finally, we show that iterative cycling of templated polymerization and activation chemistry improves the yields of random-sequence products. These results for random-sequence template copying are a significant advance in the pursuit of nonenzymatic RNA replication.
CRISPR-AsCas12f1 couples out-of-protospacer DNA unwinding with exonuclease activity in the sequential target cleavage
Authors: Song Xiaoxuan , Chen Ziting , Sun Wenjun , Yang Hao , Guo Lijuan , Zhao Yilin , Li Yanan , Ren Zhiyun , Shi Jin , Liu Cong , Ma Peixiang , Huang Xingxu , Ji Quanjiang , Sun Bo
Published: November 2024

Type V-F CRISPR-Cas12f is a group of hypercompact RNA-guided nucleases that present a versatile in vivo delivery platform for gene therapy. Upon target recognition, Acidibacillus sulfuroxidans Cas12f (AsCas12f1) distinctively engenders three DNA break sites, two of which are located outside the protospacer. Combining ensemble and single-molecule approaches, we elucidate the molecular details underlying AsCas12f1-mediated DNA cleavages. We find that following the protospacer DNA unwinding and non-target strand (NTS) DNA nicking, AsCas12f1 surprisingly carries out bidirectional exonucleolytic cleavage from the nick. Subsequently, DNA unwinding is extended to the out-of-protospacer region, and AsCas12f1 gradually digests the unwound DNA beyond the protospacer. Eventually, the single endonucleolytic target-strand DNA cleavage at 3 nt downstream of the protospacer readily dissociates the ternary AsCas12f1-sgRNA–DNA complex from the protospacer adjacent motif-distal end, leaving a staggered double-strand DNA break. The coupling between the unwinding and cleavage of both protospacer and out-of-protospacer DNA is promoted by Mg2+. Kinetic analysis on the engineered AsCas12f1-v5.1 variant identifies the only accelerated step of the protospacer NTS DNA trimming within the sequential DNA cleavage. Our findings provide a dynamic view of AsCas12f1 catalyzing DNA unwinding-coupled nucleolytic cleavage and help with practical improvements of Cas12f-based genome editing tools.
Transfer RNA supplementation rescues HARS deficiency in a humanized yeast model of Charcot-Marie-Tooth disease
Authors: Wilhelm Sarah D P , Kakadia Jenica H , Beharry Aruun , Kenana Rosan , Hoffman Kyle S , O’Donoghue Patrick , Heinemann Ilka U
Published: November 2024

Aminoacyl-tRNA synthetases are indispensable enzymes in all cells, ensuring the correct pairing of amino acids to their cognate tRNAs to maintain translation fidelity. Autosomal dominant mutations V133F and Y330C in histidyl-tRNA synthetase (HARS) cause the genetic disorder Charcot-Marie-Tooth type 2W (CMT2W). Treatments are currently restricted to symptom relief, with no therapeutic available that targets the cause of disease. We previously found that histidine supplementation alleviated phenotypic defects in a humanized yeast model of CMT2W caused by HARS V155G and S356N that also unexpectedly exacerbated the phenotype of the two HARS mutants V133F and Y330C. Here, we show that V133F destabilizes recombinant HARS protein, which is rescued in the presence of tRNAHis. HARS V133F and Y330C cause mistranslation and cause changes to the proteome without activating the integrated stress response as validated by mass spectrometry and growth defects that persist with histidine supplementation. The growth defects and reduced translation fidelity caused by V133F and Y330C mutants were rescued by supplementation with human tRNAHis in a humanized yeast model. Our results demonstrate the feasibility of cognate tRNA as a therapeutic that rescues HARS deficiency and ameliorates toxic mistranslation generated by causative alleles for CMT.
Comparative single-cell transcriptomic analysis reveals putative differentiation drivers and potential origin of vertebrate retina
Authors: Zeng Xin , Gyoja Fuki , Cui Yang , Loza Martin , Kusakabe Takehiro G , Nakai Kenta
Published: November 2024

Despite known single-cell expression profiles in vertebrate retinas, understanding of their developmental and evolutionary expression patterns among homologous cell classes remains limited. We examined and compared approximately 240 000 retinal cells from four species and found significant similarities among homologous cell classes, indicating inherent regulatory patterns. To understand these shared patterns, we constructed gene regulatory networks for each developmental stage for three of these species. We identified 690 regulons governed by 530 regulators across three species, along with 10 common cell class-specific regulators and 16 highly preserved regulons. RNA velocity analysis pinpointed conserved putative driver genes and regulators to retinal cell differentiation in both mouse and zebrafish. Investigation of the origins of retinal cells by examining conserved expression patterns between vertebrate retinal cells and invertebrate Ciona intestinalis photoreceptor-related cells implied functional similarities in light transduction mechanisms. Our findings offer insights into the evolutionarily conserved regulatory frameworks and differentiation drivers of vertebrate retinal cells.
Building electrode/electrolyte interphases in aqueous zinc batteries via self-polymerization of electrolyte additives
Authors: Geng Yaheng , Xin Wenli , Zhang Lei , Han Yu , Peng Huiling , Yang Min , Zhang Hui , Xiao Xilin , Li Junwei , Yan Zichao , Zhu Zhiqiang , Cheng Fangyi
Published: November 2024

Aqueous zinc batteries offer promising prospects for large-scale energy storage, yet their application is limited by undesired side reactions at the electrode/electrolyte interface. Here, we report a universal approach for the in situ building of an electrode/electrolyte interphase (EEI) layer on both the cathode and the anode through the self-polymerization of electrolyte additives. In an exemplified Zn||V2O5·nH2O cell, we reveal that the glutamate additive undergoes radical-initiated electro-polymerization on the cathode and polycondensation on the anode, yielding polyglutamic acid-dominated EEI layers on both electrodes. These EEI layers effectively mitigate undesired interfacial side reactions while enhancing reaction kinetics, enabling Zn||V2O5·nH2O cells to achieve a high capacity of 387 mAh g−1 at 0.2 A g−1 and maintain >96.3% capacity retention after 1500 cycles at 1 A g−1. Moreover, this interphase-forming additive exhibits broad applicability to varied cathode materials, encompassing VS2, VS4, VO2, α-MnO2, β-MnO2 and δ-MnO2. The methodology of utilizing self-polymerizable electrolyte additives to construct robust EEI layers opens a novel pathway in interphase engineering for electrode stabilization in aqueous batteries.
Efficacy and Safety of DTG/3TC for Prophylaxis of HIV Perinatal Transmission: A Pilot Study (PREGNANCY)
Authors: Brites Carlos , Luz Estela , Nóbrega Isabella , Luz Ivana , Zajdenverg Roberto , de Ruiter Annemiek , Jones Bryn , Lorenzo Cynthia R , Travassos Ana Gabriela
Published: November 2024

Background

The prevention of perinatal human immunodeficiency virus (HIV) transmission depends on the safe and effective use of antiretroviral therapy (ART). Simplifying treatment reduces drug exposure for both mother and child. We evaluated the safety and efficacy of dolutegravir (DTG) plus lamivudine (3TC) for antiretroviral-naive pregnant women with HIV.

Methods

This proof-of-concept trial enrolled ART-naive pregnant women ≥15 years old with HIV infection and a gestational age between 14 and 28 weeks. Participants received a fixed-dose combination of DTG/3TC. Baseline HIV genotyping was performed. Participants were monitored at baseline, every 4 weeks, and at delivery. Infants were assessed at birth, 4 weeks, and 6 weeks of age. Outcomes included the proportion of women achieving an undetectable HIV type 1 plasma viral load (<50 copies/mL) at delivery, therapy modification frequency, perinatal HIV transmission rate, and adverse events.

Results

Between January 2019 and March 2021, 20 women were enrolled. At baseline, the median CD4 cell count was 401.6 ± 113.6 cells/μL, increasing to 690.2 ± 266 cells/μL at delivery. Median viral load was 9514 copies/mL. All women achieved an undetectable viral load after an average of 40 days. No cases of perinatal HIV transmission were detected. No therapy modifications were necessary during the study, and no adverse events were related to the ART.

Conclusions

In this pilot trial, DTG/3TC demonstrated safety and efficacy, with all participants achieving viral suppression before delivery. There were no cases of perinatal HIV transmission and no drug-related adverse events. DTG/3TC can be an option for initial treatment of drug-naive pregnant women with HIV.
Diagnostic Value of Cross-priming Amplification Combined With CRISPR-Cas12b in Detecting Cell-free DNA in Tuberculous Pleural Effusion
Authors: Peng Lijun , Fang Tingting , Dai Lingshan , Cai Long
Published: November 2024

Background

Diagnosis of tuberculous pleural effusion (TPE) remains challenging. Studies have shown that detecting cell-free Mycobacterium tuberculosis (cf-TB) DNA in pleural effusion can improve TPE diagnosis. This study aimed to evaluate the diagnostic value of our recently developed TB One-Pot assay, which combines cross-priming amplification with CRISPR-Cas12b, in detecting cf-TB for TPE.

Methods

Pleural effusion samples were collected from inpatients with suspected TPE at Hangzhou Red Cross Hospital. After centrifugation, the precipitate was used for culture, Xpert, and pleural effusion cytologic testing, while the supernatant was used for biochemical and cf-TB assays, including TB One-Pot and the quantitative polymerase chain reaction method (cf-TB-PCR). Assessment of diagnostic performance was based on a comprehensive reference standard.

Results

A total of 115 patients were included: 88 TPE cases (diagnosed per the comprehensive reference standard) and 27 non-TPE cases. The sensitivity of TB One-Pot in detecting pleural cf-TB for diagnosing TPE was 64.8%, with an area under the curve (AUC) of 0.805, significantly superior to culture and Xpert (P < .05). When compared with cf-TB-PCR (sensitivity, 53.4%; AUC, 0.767) and the adenosine deaminase assay (sensitivity, 52.3%; AUC, 0.761), TB One-Pot demonstrated slightly higher sensitivity and AUC, but the differences were not statistically significant (P > .05). The specificity of TB One-Pot was 96.3%, while the specificity of the other tests was 100%, with no statistically significant differences (P > .05).

Conclusions

cf-TB provides direct evidence of the etiology of TPE. TB One-Pot for detecting cf-TB in diagnosing TPE outperforms existing TB laboratory tests and may represent a more effective approach for TPE diagnosis in resource-limited settings.
Genomic alterations associated with early-stage disease and early recurrence in patients with colorectal cancer
Authors: Pappas Leontios , Quintanilha Julia C F , Huang Richard S P , Parikh Aparna R
Published: November 2024

Background

The molecular characterization of early-stage (1-3) colorectal cancer (CRC) remains incomplete, as opposed to metastatic disease, where comprehensive genomic profiling (CGP) is routinely performed. This study aimed to characterize the genomics of stages 1-3 versus IV CRC, and the genomics of patients recurring within 1 year of diagnosis.

Patients and Methods

Patients from a de-identified CRC clinico-genomic database who received Foundation Medicine testing (FoundationOne/FoundationOne CDx) during routine clinical care at approximately 280 US cancer clinics between March 2014 and June 2023 were included. Genomic alterations (GA) were compared by Fisher’s exact test.

Results

A total of 4702 patients were included; 1902 with stages 1-3 and 2800 with stage 4 disease. Among patients with stages 1-3 disease, 546 recurred within 1 year. Patients staged 1-3 had higher prevalence of microsatellite instability (MSI-H, 11.4% vs 4.5%, P < .001), tumor mutational burden (TMB) ≥ 10 Mut/Mb (14.6% vs 6.8%, P < .001), GA in RNF43 (11.2% vs 5.7%, P < .001), MSH6 (3.9% vs 1.7%, P < .001), MLH1 (2.3% vs 0.7%, P < .001), and MSH2 (1.5% vs 0.6%, P < .01) compared to those with stage 4 disease. Patients who recurred within 1 year had higher prevalence of MSI-H (13.2% vs 4.4%, P < .001), TMB ≥ 10 Mut/Mb (16.2% vs 6.9%, P < .001), BRAF V600E (17.2% vs 7.9%, P < .003), GA in RNF43 (13.7% vs 5.3%, P < .001), MSH6 (4.2% vs 1.6%, P = .035), and BRCA1/2 (6.2% vs 3.0%, P = .030). On recurrence, more patients received targeted therapy when CGP was performed before versus after first-line therapy (43% vs 19%, P < .001).

Conclusions

Early-stage CRC patients can have distinct genomic profiles and CGP in this population can help expand access to targeted therapies.
Predicative Classes and Strict Potentialism
Authors: Linnebo Øystein , Shapiro Stewart
Published: November 2024

While sets are combinatorial collections, defined by their elements, classes are logical collections, defined by their membership conditions. We develop, in a potentialist setting, a predicative approach to (logical) classes of (combinatorial) sets. Some reasons emerge to adopt a stricter form of potentialism, which insists, not only that each object is generated at some stage of an incompletable process, but also that each truth is “made true” at some such stage. The natural logic of this strict form of potentialism is semi-intuitionistic: where each set-sized domain is classical, the domain of all sets or all classes is intuitionistic.
Complexity data science: A spin-off from digital twins
Authors: Emmert-Streib Frank , Cherifi Hocine , Kaski Kimmo , Kauffman Stuart , Yli-Harja Olli
Published: November 2024

Digital twins offer a new and exciting framework that has recently attracted significant interest in fields such as oncology, immunology, and cardiology. The basic idea of a digital twin is to combine simulation and learning to create a virtual model of a physical object. In this paper, we explore how the concept of digital twins can be generalized into a broader, overarching field. From a theoretical standpoint, this generalization is achieved by recognizing that the duality of a digital twin fundamentally connects complexity science with data science, leading to the emergence of complexity data science as a synthesis of the two. We examine the broader implications of this field, including its historical roots, challenges, and opportunities.
Numerical Version of the Complex-Scaling Green’s Operator Method
Authors: Yamasaki N , Fumimoto T , Maeda T , Ito M
Published: November 2024

A new treatment of scattering problems is formulated by improving the complex-scaling Green’s operator (CSGO) method, which can calculate the transition or scattering matrix from the spectral representation of the complex-scaled Green’s function and the asymptotic solution expressed in terms of the analytic function. In the present formulation, the CSGO method is extended to handle the general scattering problem in charged-particle systems by employing the Coulomb wave function numerically calculated under the complex-scaled asymptotic Hamiltonian. We call the new method the CSGO-numerical (CSGON) method, and it is applied to the scattering problem of the $^4$He + proton system to check its validity. The continuum level density (CLD) method, which is another method to solve the scattering problem, is also applied to the same system. The numerical precision and the applicability of the CSGON method is discussed by comparing it with the CLD and CSGO methods.
eIF6 modulates skin wound healing by upregulating keratin 6B
Authors: Wang Xiaoyan , Xu Guangchao , Zhang Fangyingnan , Wei Yating , Deng Jiawen , Mu Lan , He Jinqing , He Dehua , Yin Meifang , Dal Pra Ilaria , Liu Xiaofang , Cai Weichao , Yang Linjing , Han Chunmao , Huang Guangtao , Wu Jun
Published: November 2024

Eukaryotic translation initiation factor 6 (eIF6) plays a crucial role in 60S ribosome biogenesis and protein translation, as well as in hypertrophic scar formation, but its potential role in epithelialization is still poorly understood. Herein, we found that eIF6 negatively correlated with the wound healing process. Mice with genetically knockdown eIF6 (eIF6+/−) showed faster re-epithelization as shown by the longer tongue of the newly formed epidermis. Furthermore, eIF6 ablation accelerated the wound healing process by targeting basal keratinocytes in the eIF6 keratinocyte-conditional knockout (eIF6f/+; Krt5-Cre+) mice. Mechanistically, keratin 6B, an important wound-activated protein, was significantly upregulated in eIF6f/+; Krt5-Cre+ mice skin as proved by RNA-seq, western immunoblots, and immunofluorescence staining. Moreover, an elevated level of KRT6B and accelerated proliferative capacity were also observed in stable knockdown eIF6 HaCaT cells. Taken together, eIF6 downregulation could accelerate epithelialization by upregulating KRT6B expression and promoting keratinocyte proliferation. Our results for the first time indicate that eIF6 might be a novel target to regulate re-epithelialization.
#PorkandPigs: an online media listening analysis of public perception of the U.S. swine industry
Authors: Fisk Alexandra E , Smith Michael L , Richert Brian T , Olynk Widmar Nicole J
Published: November 2024

With the majority of the U.S. swine industry being generally bounded by social licensing, there is a growing need to understand social perspectives to better adapt to consumer demands. Online and social media data are rich datasets that researchers are leveraging to tackle economic and societal challenges. The information that can be gleaned from online media regarding public perceptions makes it an important tool for producers to understand driving topics of interest to the public. This study utilized a prominent online and social media listening and data analytics platform to identify and quantify online and social media mentions related to the U.S. swine industry from January 1, 2020, to December 31, 2023. A general search for online media referencing pork and pigs was designed resulting in a total of 41,093,309 mentions. The search was further queried to specific topics of food and cooking (20,580,068 mentions), price (2,866,548 mentions), welfare (1,615,208 mentions), sustainability (771,819 mentions), and top authors/organizations within the U.S. swine industry (1,430 mentions). The study spanned the geographic locations of the overall US (including U.S. Minor Outlying Islands), the top 5 most populous states, and the top 5 pork-producing states as of 2024. Of all mentions, X/Twitter was the largest domain for nearly all mentions related to pork and pigs. Major organizations designed to spread information between the general public and pork producers had a minor impact on the overall conversation and no online media presence in the top 5 most populous states. Net sentiment was overall positive across all 4 yr and all geographies except for major events such as the COVID-19 pandemic, the H1N1 Swine Flu, the passing of California Proposition 12, environmental events, and inflation-associated pork prices. Overall, most media presence had positive net sentiments and with most interest surrounding ways to cook pork and how to keep bacon cheap. Understanding public perceptions of the U.S. swine industry provides the opportunity to make informed decisions on marketing strategies and production practices.
Young Black and White adults prefer in-person to telehealth for primary care visits and group health promotion programs
Authors: Gavrilova Lyubov , Watson Mellisa C , Eshera Yasmine M , Ridgel Angela L , Hughes Joel W
Published: November 2024

Telehealth utilization has increased since the coronavirus disease 2019 pandemic, reducing barriers to healthcare and, potentially, reducing participation in group health-promotion interventions. However, preferences for telehealth versus in-person formats have not been established. To examine preferences for telehealth and in-person format for primary care and group health-promotion interventions among Black and White women and men aged 20–39. We hypothesized that respondents would report a higher preference for telehealth than in-person appointments. This cross-sectional survey study recruited participants to answer questions about access to technology and preferences for telehealth and in-person formats of primary care and group health promotion. Respondents (n = 404) included similar proportions of White women (24.3%, 26.4 ± 4.3 years), Black women (25.0%, 29.0 ± 6.1 years), White men (25.9%, 32.8 ± 4.5 years), and Black men (24.8%, 30.6 ± 5.2 years). About 98.5% reported having a smartphone, and 80.4% had access to a computer with a camera. Preference ratings were higher for in-person visits, compared to telehealth visits, for both primary care (M = 3.86 ± 1.13 vs. M = 2.87 ± 1.18) and group health promotion (M = 3.72 ± 1.12 vs. M = 3.04 ± 1.20) F’s(1,400) > 59.0, P’s < .001. Most young adults have access to technology, supporting the feasibility of telehealth interventions. However, telehealth preference ratings were lower than in-person appointments. Preferences for delivery formats should be considered when designing behavioral interventions to promote health and prevent disease.
A unique compound ameliorating endoplasmic reticulum stress and insulin resistance by binding to β tubulin
Authors: Horiuchi Keigo , Matsushima Goshi , Wada Momoe , Thon Mina , Sobhy Mohamed Hossam , Ayoub Ahmed Taha , Hara Misato , Yoshii Michiko , Arakawa Kenji , Ozawa Koichiro , Hosoi Toru
Published: November 2024

Insulin is secreted by the pancreatic β‐cells and regulates glucose uptake. Endoplasmic reticulum (ER) stress is known to induce insulin resistance. Identifying novel compounds, which can ameliorate ER stress and insulin resistance may be beneficial in the treatment of diabetes. Since treatment with compounds sourced from edible plants is relatively safe, this study aimed to identify a plant‐derived potential compound attenuating insulin resistance. In the present study, we identified apigenin as an effective compound for ameliorating ER stress and insulin resistance. It attenuated ER stress‐induced cell death and hepatic insulin resistance and improved abnormal glucose tolerance in a db/db diabetic model. The molecular mechanism of apigenin involved direct binding to β‐tubulin and improving tubulin stability, thereby recovering insulin resistance and developing diabetes. To our knowledge, no known antidiabetic drugs are yet known to target β‐tubulin. Edible plants containing apigenins, such as onions, oranges, and parsley, have been consumed since a long time. Therefore, the use of natural edible plants as a source may offer a safe strategy for the prevention of diabetes.
Hemin promotes platelet activation and plasma membrane disintegration regulated by the subtilisin‐like proprotein convertase furin
Authors: Schaale David , Laspa Zoi , Balmes Aylin , Sigle Manuel , Dicenta‐Baunach Valerie , Hochuli Ravi , Fu Xiaoqing , Serafimov Kristian , Castor Tatsiana , Harm Tobias , Müller Karin Anne Lydia , Rohlfing Anne‐Katrin , Laufer Stefan , Schäffer Tilman E. , Lämmerhofer Michael , Gawaz Meinrad
Published: November 2024

Platelet activation plays a critical role in thrombosis and hemostasis. Several pathophysiological situations lead to hemolysis, resulting in the liberation of free ferric iron‐containing hemin. Hemin has been shown to activate platelets and induce thrombo‐inflammation. Classical antiplatelet therapy failed to prevent hemin‐induced platelet activation. Thus, the aim of the present study was to characterize the mechanism of hemin‐induced platelet death (ferroptosis). We evaluated the in vitro effect of hemin on platelet activation, signaling, oxylipins, and plasma membrane destruction using light transmission aggregometry, ex vivo thrombus formation, multiparametric flow cytometry, micro‐UHPLC mass spectrometry for oxylipin profiling, and scanning ion conductance microscopy (SICM). We found that hemin induces platelet cell death indicated by increased ROS levels, phosphatidyl serine (PS) exposure, and loss of mitochondrial membrane potential (ΔΨm). Further, hemin causes lipid peroxidation and generation of distinct oxylipins, which strongly affects plasma membrane integrity leading to generation of platelet‐derived microvesicles. Interestingly, hemin‐dependent platelet death (ferroptosis) is specifically regulated by the subtilisin‐like proprotein convertase furin. In summary, platelet undergo a non‐apoptotic cell death mediated by furin. Inhibition of furin may offer a therapeutic strategy to control hemin‐induced thrombosis and thrombo‐inflammation at a site of hemolysis.
Prime editing: A gene precision editing tool from inception to present
Authors: Liu Zhihao , Guo Dong , Wang Dawei , Zhou Jinglin , Chen Qi , Lai Junzhong
Published: November 2024

Genetic mutations significantly contribute to the onset of diseases, with over half of the cases caused by single‐nucleotide mutations. Advances in gene editing technologies have enabled precise editing and correction of mutated genes, offering effective treatment methods for genetic disorders. CRISPR/Cas9, despite its power, poses risks of inducing gene mutations due to DNA double‐strand breaks (DSB). The advent of base editing (BE) and prime editing (PE) has mitigated these risks by eliminating the hazards associated with DNA DSBs, allowing for more precise gene editing. This breakthrough lays a solid foundation for the clinical application of gene editing technologies. This review discusses the principles, development, and applications of PE gene editing technology in various genetic mutation‐induced diseases.
The whole‐body and skeletal muscle metabolic response to 14 days of highly controlled low energy availability in endurance‐trained females
Authors: Caldwell Hannah G. , Jeppesen Jan S. , Lossius Lone O. , Atti Jesper P. , Durrer Cody G. , Oxfeldt Mikkel , Melin Anna K. , Hansen Mette , Bangsbo Jens , Gliemann Lasse , Hellsten Ylva
Published: November 2024

This study investigated the effects of 14 days low energy availability (LEA) versus optimal energy availability (OEA) in endurance‐trained females on substrate utilization, insulin sensitivity, and skeletal muscle mitochondrial oxidative capacity; and the impact of metabolic changes on exercise performance. Twelve endurance‐trained females (V̇O2max 55.2 ± 5.1 mL × min−1 × kg−1) completed two 14‐day randomized, blinded, cross‐over, controlled dietary interventions: (1) OEA (51.9 ± 2.0 kcal × kg fat‐free mass (FFM)−1 × day−1) and (2) LEA (22.3 ± 1.5 kcal × kg FFM−1 × day−1), followed by 3 days OEA. Participants maintained their exercise training volume during both interventions (approx. 8 h × week−1 at 79% heart rate max). Skeletal muscle mitochondrial respiratory capacity, glycogen, and maximal activity of CS, HAD, and PFK were unaltered with LEA. 20‐min time trial endurance performance was impaired by 7.8% (Δ −16.8 W, 95% CI: −23.3 to −10.4, p < .001) which persisted following 3 days refueling post‐LEA (p < .001). Fat utilization was increased post‐LEA as evidenced by: (1) 99.4% (p < .001) increase in resting plasma free fatty acids (FFA); (2) 270% (p = .007) larger reduction in FFA in response to acute exercise; and (3) 28.2% (p = .015) increase in resting fat oxidation which persisted during submaximal exercise (p < .001). These responses were reversed with 3 days refueling. Daily glucose control (via CGM), HOMA‐IR, HOMA‐β, were unaffected by LEA. Skeletal muscle O2 utilization and carbohydrate availability were not limiting factors for aerobic exercise capacity and performance; therefore, whether LEA per se affects aspects of training quality/recovery requires investigation.
CD3D silencing alleviates diabetic nephropathy via inhibition of JAK/STAT pathway
Authors: Lei Xianghong , Zou Fangqin , Tang Xianhu , He Fengxia , Wang Jiyang , Cheng Shengyu , Lei Xiangxin
Published: November 2024

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes that poses a significant burden to global health. This investigation aims to illustrate the functional role of CD3D and its relevant mechanisms in DN progression. The pivotal genes between the GSE47183 and GSE30528 datasets were identified using bioinformatics methods. The effects of CD3D silencing on renal damage, inflammatory response, and lipid metabolism were validated in DN mice. Furthermore, the impacts of CD3D knockdown on cell viability, apoptotic rate, inflammation, and lipid levels were investigated in HK‐2 cells under high glucose (HG) conditions. Additionally, RO8191 was employed to investigate the role of CD3D in the JAK/STAT pathway in HG‐treated cells. A total of 5 focal genes were identified through bioinformatics and were found to be upregulated in renal tissues from DN mice. CD3D silencing mitigated pathological damage to kidneys, reduced inflammatory response, and decreased lipid accumulation in DN mice. HG stimulation restrained viability, increased apoptosis, promoted the release of inflammatory cytokines, and affected expressions of hallmarks related to lipid metabolism in HG‐treated cells; these changes were partially abolished by CD3D knockdown. Mechanistically, CD3D downregulation ameliorated HG‐induced injury in HK‐2 cells by blocking the JAK/STAT pathway. This study underscores that CD3D silencing has significant potential as a promising candidate in the treatment of DN.
EHD1 promotes breast cancer metastasis through upregulating HIF2a expression via activating mTOR pathway
Authors: Gao Xiaoqian , Li Juan , Feng Xuefei , Xie Yuchen , Zhang Juan , Liu Jie , Wang Bo , Liu Peijun
Published: November 2024

The multistep dynamic process of metastasis is the primary cause of breast cancer deaths. C‐terminal Eps15‐homology domain‐containing protein 1 (EHD1), a translocator associated with endocytic recycling, has been implicated in various oncogenic processes. However, the precise molecular mechanisms of EHD1‐induced breast cancer metastases remain largely unexplored. Here we found that the upregulation of EHD1 in breast cancer was positively associated with distant lymph node metastasis in patients. Meanwhile, EHD1 promoted epithelial‐mesenchymal transition (EMT), invasion, and metastasis of breast cancer cells in both two‐dimensional (2D) and three‐dimensional (3D) culture models in vitro, as well as in vivo. Remarkably, EHD1 can activate the AKT–mTOR pathway to upregulate the protein expression of hypoxia‐inducible factor 2α (HIF2α) under normoxic conditions and subsequently enhance the invasive and metastatic breast cancer. Our findings indicated EHD1 as a new regulator of HIF2α and a potential therapeutic target for inhibiting breast cancer metastasis.