bluuebunny/crossref_metadata_2025 huggingface dataset:
Co-evolution of vaginal microbiome and cervical cancer
Authors: Hu Menglu , Yang Wentao , Yan Ruiyi , Chi Jiayu , Xia Qi , Yang Yilin , Wang Yinhan , Sun Lejia , Li Ping
Published: June 2024

Background

Exploration of adaptive evolutionary changes at the genetic level in vaginal microbial communities during different stages of cervical cancer remains limited. This study aimed to elucidate the mutational profile of the vaginal microbiota throughout the progression of cervical disease and subsequently establish diagnostic models.

Methods

This study utilized a metagenomic dataset consisting of 151 subjects classified into four categories: invasive cervical cancer (CC) (n = 42), cervical intraepithelial neoplasia (CIN) (n = 43), HPV-infected (HPVi) patients without cervical lesions (n = 34), and healthy controls (n = 32). The analysis focused on changes in microbiome abundance and extracted information on genetic variation. Consequently, comprehensive multimodal microbial signatures associated with CC, encompassing taxonomic alterations, mutation signatures, and enriched metabolic functional pathways, were identified. Diagnostic models for predicting CC were established considering gene characteristics based on single nucleotide variants (SNVs).

Results

In this study, we screened and analyzed the abundances of 18 key microbial strains during CC progression. Additionally, 71,6358 non-redundant mutations were identified, predominantly consisting of SNVs that were further annotated into 25,773 genes. Altered abundances of SNVs and mutation types were observed across the four groups. Specifically, there were 9847 SNVs in the HPV-infected group and 14,892 in the CC group. Furthermore, two distinct mutation signatures corresponding to the benign and malignant groups were identified. The enriched metabolic pathways showed limited similarity with only two overlapping pathways among the four groups. HPVi patients exhibited active nucleotide biosynthesis, whereas patients with CC demonstrated a significantly higher abundance of signaling and cellular-associated protein families. In contrast, healthy controls showed a distinct enrichment in sugar metabolism. Moreover, biomarkers based on microbial SNV abundance displayed stronger diagnostic capability (cc.AUC = 0.87) than the species-level biomarkers (cc.AUC = 0.78). Ultimately, the integration of multimodal biomarkers demonstrated optimal performance for accurately identifying different cervical statuses (cc.AUC = 0.86), with an acceptable performance (AUC = 0.79) in the external testing set.

Conclusions

The vaginal microbiome exhibits specific SNV evolution in conjunction with the progression of CC, and serves as a specific biomarker for distinguishing between different statuses of cervical disease.
Entomophagy and entomo-therapeutic practices in a mountainous territory in southeast Guangxi Zhuang Autonomous Region, China
Authors: Luo Huimin , Dai Chuanyin , Feng Ping
Published: June 2024

Background

Although China has a long history of using insects as food and medicine and has developed numerous associated knowledge and practices, especially in its rural and mountainous areas, systematic surveys concerning this subject are limited. In-depth ethnobiological research is needed to compile a comprehensive database of edible and medicinal insects and record the associated knowledge of these food and medicinal resources.

Methods

Data on edible and medicinal insects and associated knowledge about them were collected by interviewing 216 local villagers in a mountainous territory in southeast Guangxi Zhuang Autonomous Region, China.

Results

Local villagers used at least 16 edible and 9 medicinal insects, of which 4 wasp species were used in both entomophagy and medicinal practices. Parapolybia varia, Polistes olivaceus, and Anomala chamaeleon were newly recorded edible insects in China. The wasps, Euconocephalus sp., Gryllotalpa orientalis, and Cyrtotrachelus longimanus, were preferred and culturally important edible insects. Populations of Euconocephalus sp. and G. orientalis were reported to have substantially decreased in recent years. Wasps and a bamboo bee were used to treat rheumatism, while cockroaches and antlions were used to treat common cold symptoms in infants. Insect-related knowledge was positively correlated with the interviewees’ age.

Conclusions

Villagers have accumulated considerable local and traditional knowledge of entomophagy and entomo-therapeutic practices. However, this knowledge is in danger of being lost, which highlights the urgent need to document this information. Edible insects enrich local diets, and a more sustainable supply (such as through insect farming) could maintain local entomophagy practices. Medicinal insects are a part of local folk medicine, and pharmacological and chemical techniques could be applied to identify various biologically active substances in these insects.
Internal initiation of reverse transcription in a Penelope-like retrotransposon
Authors: Frangieh Chris J. , Wilkinson Max E. , Strebinger Daniel , Strecker Jonathan , Walsh Michelle L. , Faure Guilhem , Yushenova Irina A. , Macrae Rhiannon K. , Arkhipova Irina R. , Zhang Feng
Published: June 2024

Eukaryotic retroelements are generally divided into two classes: long terminal repeat (LTR) retrotransposons and non-LTR retrotransposons. A third class of eukaryotic retroelement, the Penelope-like elements (PLEs), has been well-characterized bioinformatically, but relatively little is known about the transposition mechanism of these elements. PLEs share some features with the R2 retrotransposon from Bombyx mori, which uses a target-primed reverse transcription (TPRT) mechanism, but their distinct phylogeny suggests PLEs may utilize a novel mechanism of mobilization. Using protein purified from E. coli, we report unique in vitro properties of a PLE from the green anole (Anolis carolinensis), revealing mechanistic aspects not shared by other retrotransposons. We found that reverse transcription is initiated at two adjacent sites within the transposon RNA that is not homologous to the cleaved DNA, a feature that is reflected in the genomic “tail” signature shared between and unique to PLEs. Our results for the first active PLE in vitro provide a starting point for understanding PLE mobilization and biology.
Evaluation of bovine coronavirus in Korean native calves challenged through different inoculation routes
Authors: Cho Hyung-Chul , Kim Youngjun , Cho Yong-Il , Park Jinho , Choi Kyoung-Seong
Published: June 2024

Bovine coronavirus (BCoV) is a pneumoenteric virus that can infect the digestive and respiratory tracts of cattle, resulting in economic losses. Despite its significance, information regarding BCoV pathogenesis is limited. Hence, we investigated clinical signs, patterns of viral shedding, changes in antibody abundance, and cytokine/chemokine production in calves inoculated with BCoV via intranasal and oral. Six clinically healthy Korean native calves (< 30 days old), initially negative for BCoV, were divided into intranasal and oral groups and monitored for 15 days post-infection (dpi). BCoV-infected calves exhibited clinical signs such as nasal discharge and diarrhea, starting at 3 dpi and recovering by 12 dpi, with nasal discharge being the most common symptoms. Viral RNA was detected in nasal and fecal samples from all infected calves. Nasal shedding occurred before fecal shedding regardless of the inoculation route; however, fecal shedding persisted longer. Although the number of partitions was very few, viral RNA was identified in the blood of two calves in the oral group at 7 dpi and 9 dpi using digital RT-PCR analysis. The effectiveness of maternal antibodies in preventing viral replication and shedding appeared limited. Our results showed interleukin (IL)-8 as the most common and highly induced chemokine. During BCoV infection, the levels of IL-8, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1β were significantly affected, suggesting that these emerge as potential and reliable biomarkers for predicting BCoV infection. This study underscores the importance of BCoV as a major pathogen causing diarrhea and respiratory disease.
Stress drops of intermediate-depth intraslab earthquakes beneath Tohoku, northern Japan
Authors: Kita Saeko , Shiina Takahiro , Houston Heidi , Shiomi Katsuhiko
Published: June 2024

We calculated stress drops for 2875 small intraslab earthquakes at intermediate depths beneath Tohoku, Japan. We applied an S-coda-wave spectral ratio method to almost 900,000 event pairs. Detailed velocity values for the oceanic crust (OC) were adopted from previous observational studies. The median stress drops in the OC are about half those in the oceanic mantle (OM). The median stress drop for earthquakes in the OC decreases from depths of 70 to 120 km and increases from 120 to 170 km. Our preferred interpretation is that the rigidity in the OC decreases and then increases with depth due to combined effects of the dehydration associated with the eclogite formation and the increasing temperature with depth. These depth variations are consistent with results of a similar study beneath Hokkaido. The median stress drops in the oceanic plate beneath Tohoku are generally smaller than those beneath Hokkaido. Previous studies imaging the seismic structure at shallow depths and b-value analyses of intraslab earthquakes indicate that the near-trench region of the oceanic plate off Tohoku is more hydrated than that off Hokkaido. Taken together, these results suggest that differences in the degree of hydration of the oceanic plate in the near-trench regions could produce the different behaviors of stress drops of intermediate-depth earthquakes observed in Tohoku and Hokkaido.

Graphical Abstract
Genome-wide enhancer RNA profiling adds molecular links between genetic variation and human cancers
Authors: Cai Yi-Min , Lu Ze-Qun , Li Bin , Huang Jin-Yu , Zhang Ming , Chen Can , Fan Lin-Yun , Ma Qian-Ying , He Chun-Yi , Chen Shuo-Ni , Jiang Yuan , Li Yan-Min , Ning Cai-Bo , Zhang Fu-Wei , Wang Wen-Zhuo , Liu Yi-Zhuo , Zhang Heng , Jin Meng , Wang Xiao-Yang , Han Jin-Xin , Xiong Zhen , Cai Ming , Huang Chao-Qun , Yang Xiao-Jun , Zhu Xu , Zhu Ying , Miao Xiao-Ping , Zhang Shao-Kai , Wei Yong-Chang , Tian Jian-Bo
Published: June 2024

Background

Dysregulation of enhancer transcription occurs in multiple cancers. Enhancer RNAs (eRNAs) are transcribed products from enhancers that play critical roles in transcriptional control. Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers.

Methods

Initially, a comprehensive analysis of eRNA quantitative trait loci (eRNAQTLs) was performed in The Cancer Genome Atlas (TCGA), and functional features were characterized using multi-omics data. To establish the first eRNAQTL profiles for colorectal cancer (CRC) in China, epigenomic data were used to define active enhancers, which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples. Finally, large-scale case-control studies (34,585 cases and 69,544 controls) were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk.

Results

A total of 300,112 eRNAQTLs were identified across 30 different cancer types, which exert their influence on eRNA transcription by modulating chromatin status, binding affinity to transcription factors and RNA-binding proteins. These eRNAQTLs were found to be significantly enriched in cancer risk loci, explaining a substantial proportion of cancer heritability. Additionally, tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer. Moreover, the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer, highlighting their potential as therapeutic targets. Furthermore, multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China (OR = 0.91, 95%CI 0.88–0.95, P = 2.92 × 10−7) and Europe (OR = 0.92, 95%CI 0.88–0.95, P = 4.61 × 10−6). Mechanistically, rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786, which functioned as a transcriptional activator promoting the expression of its target gene SENP7. These two genes synergistically suppressed tumor cell proliferation. Our curated list of variants, genes, and drugs has been made available in CancereRNAQTL (http://canernaqtl.whu.edu.cn/#/) to serve as an informative resource for advancing this field.

Conclusion

Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.
Collaborating with cancer patients and informal caregivers in a European study on quality of life: protocol to embed patient and public involvement within the EUonQoL project
Authors: Engelaar Merel , Bos Nanne , van Schelven Femke , Lorenzo i Sunyer Nora , Couespel Norbert , Apolone Giovanni , Brunelli Cinzia , Caraceni Augusto , Ferrer Montse , Groenvold Mogens , Kaasa Stein , Ciliberto Gennaro , Lombardo Claudio , Pietrobon Ricardo , Pravettoni Gabriella , Sirven Aude , Vachon Hugo , Gilbert Alexandra , Rademakers Jany
Published: June 2024

Background

Patient and public involvement (PPI) has become an essential part of health research. There is a need for genuine involvement in order to ensure that research is relevant to patients. This can then improve the quality, relevance, and impact of health research, while at the same time reducing wasted research and in doing so bringing science and society closer together. Despite the increasing attention for this involvement, it is not yet common practice to report on proposed activities. An article reporting planned PPI could provide guidance and inspiration for the wider academic community in future activities. Therefore, this current article aims to describe the way in which PPI principles are incorporated in the research project called “Quality of Life in Oncology: measuring what matters for cancer patients and survivors in Europe (EUonQoL).” This project aims to develop a new set of questionnaires to enable cancer patients to assess their quality of life, entitled the EUonQoL-Kit.

Methods

The first step is to recruit cancer patients and their informal caregivers as co-researchers in order to train them to collaborate with the researchers. Based on their skills and preferences, they are then assigned to several of the project’s work packages. Their individual roles, tasks, and responsibilities regarding the work packages, to which they have been assigned, are evaluated and adapted when necessary. The impact of their involvement is evaluated by both the researchers and co-researchers.

Discussion

PPI is a complex and dynamic process. As such, the overall structure of the research may be defined while at the same time leaving room for certain aspects to be filled in later. Our research is, we believe, relevant as co-researcher involvement in such a large European project as EUonQoL is a new development.
The complete mitochondrial genomes of five critical phytopathogenic Bipolaris species: features, evolution, and phylogeny
Authors: Song Xinzheng , Geng Yuehua , Xu Chao , Li Jiaxin , Guo Yashuang , Shi Yan , Ma Qingzhou , Li Qiang , Zhang Meng
Published: June 2024

In the present study, three mitogenomes from the Bipolaris genus (Bipolaris maydis, B. zeicola, and B. oryzae) were assembled and compared with the other two reported Bipolaris mitogenomes (B. oryzae and B. sorokiniana). The five mitogenomes were all circular DNA molecules, with lengths ranging from 106,403 bp to 135,790 bp. The mitogenomes of the five Bipolaris species mainly comprised the same set of 13 core protein-coding genes (PCGs), two rRNAs, and a certain number of tRNAs and unidentified open reading frames (ORFs). The PCG length, AT skew and GC skew showed large variability among the 13 PCGs in the five mitogenomes. Across the 13 core PCGs tested, nad6 had the least genetic distance among the 16 Pleosporales species we investigated, indicating that this gene was highly conserved. In addition, the Ka/Ks values for all 12 core PCGs (excluding rps3) were < 1, suggesting that these genes were subject to purifying selection. Comparative mitogenomic analyses indicate that introns were the main factor contributing to the size variation of Bipolaris mitogenomes. The introns of the cox1 gene experienced frequent gain/loss events in Pleosporales species. The gene arrangement and collinearity in the mitogenomes of the five Bipolaris species were almost highly conserved within the genus. Phylogenetic analysis based on combined mitochondrial gene datasets showed that the five Bipolaris species formed well-supported topologies. This study is the first report on the mitogenomes of B. maydis and B. zeicola, as well as the first comparison of mitogenomes among Bipolaris species. The findings of this study will further advance investigations into the population genetics, evolution, and genomics of Bipolaris species.
Myopericarditis revealing a systemic sclerosis-systemic lupus erythematosus overlap syndrome complicated by fatal cytomegalovirus infection: a case report
Authors: Bennani Ghali , Zahri Soukaina , Boulahnach Anas , Drighil Abdenasser , Habbal Rachida
Published: June 2024

Background

Systemic sclerosis (SSc)-systemic lupus erythematosus (SLE) overlap syndrome is rarely described in the literature, and its morbidity and mortality remain high after the early onset of pulmonary arterial hypertension (PAH), which determines its severity. The epidemiology of SSc-SLE overlap syndrome is not well known. It is characterized by high clinical polymorphism, making its diagnosis difficult. Through this case, we underline the difficulty and delay in the diagnosis of this syndrome in a country with limited resources, as well as the difficulty of its management given the specificity of the treatment for each pathology and the risk of infections, which could limit their use.

Case presentation

We report the case of a 49-year-old North African female patient, initially followed for SSc for 8 years, whose diversity of symptoms masked the distinct disease. Indeed, her initial clinical presentation was in favor of SSc, but the discovery of a pericardial effusion stimulated us to carry out more investigations and correct the initial diagnosis. The involvement of the myocardium and pericardium, as well as the positive antibody serology tests, make it possible to retain the diagnosis of SSc-SLE overlap syndrome. Despite the introduction of treatment, the patient unfortunately died a month later after developing a multi organ failure following an opportunistic infection.

Conclusions

The management of SSc-SLE overlap syndrome can be complex, requiring good knowledge of these two pathologies, especially in immunocompromised patients with complications. Treatments based on corticosteroids and immunosuppressants may differ from one case to another, making their use difficult in a patient developing a cytomegalovirus (CMV) infection. These patients require urgent treatment before the onset of complications, at the risk of worsening the prognosis, with close collaboration between a cardiologist and an internist, given the multisystem involvement.
Innovations in Rare Gynecologic Cancer: Melanoma, Neuroendocrine, and Low-Grade Serous Ovarian
Authors: Au-Yeung George , MacArthur Emily , Chan Joanna , Ilenkovan Narthana , Frumovitz Michael , Fader Amanda N. , Gourley Charlie
Published: June 2024

In the field of gynecologic cancer, low-grade serous ovarian cancer (LGSOC) has been poorly understood and underinvestigated until recently. Similarly, understanding of the distinct properties and therapeutic sensitivities of gynecologic melanoma and cervical neuroendocrine tumors has recently accelerated. For each of these rare cancers, we explore the epidemiology and natural history, discuss the prognosis, diagnostic testing, and contemporary molecular classification, and then deliberate existing and emerging therapeutic strategies. In LGSOC, we focus on the clinical relevance of recent molecular studies that shed light on the importance of mitogen-activated protein kinase (MAPK) pathway gene mutation and chromosome 1 copy-number change on prognosis and MEK inhibitor sensitivity. We also discuss the relative chemoresistance of this disease and the fact that attention is shifting to combinations of molecular therapies such as endocrine agents plus cyclin-dependent kinase 4/6 inhibitors or MEK inhibitors plus FAK inhibitors. Gynecologic tract melanomas harbor a lower frequency of canonical BRAF mutations, and have lower tumor mutational burden and immune cell infiltration than cutaneous melanomas (CMs). As a result, patients with this disease are less likely to respond to BRAF/MEK or immune checkpoint inhibition than patients with CM. Emerging strategies include the combination of antiangiogenic agents with immune checkpoint inhibitors and the use of adoptive cellular therapies. In cervical neuroendocrine cancer, we discuss the use of surgery in early-stage disease, and the uncertainties regarding the role of radiotherapy. We also explore the evidence for chemotherapy and emerging investigational strategies including the use of poly (ADP-ribose) polymerase inhibitors. For all situations, we explore the shared decision-making process with the patient.
Long-term efficacy of high-dose imatinib in Hispanic patients without access to second-generation tyrosine kinase inhibitors treated in LATAM centers.
Authors: Dorsey Trevino Edgar , Cantu-Rodriguez Olga Graciela , Osorno-Rodriguez Karen Lorena , Gutierrez-Aguirre Cesar Homero , Jaime-Perez Jose Carlos , Gomez-Villarreal Juan Pablo , Rios-Rodelo Miguel Ricardo , Gonzalez-Cantu Graciela Alejandra , Contreras-Arce Alan , Gomez-Almaguer David
Published: June 2024

6512

Background: Treatment for patients with chronic myeloid leukemia (CML) had a benchmark with the introduction of imatinib, a tyrosine kinase inhibitor (TKI). Nevertheless, resistance due to genetic mutations in the BCR::ABL1 kinase receptor remains relatively common for many patients, leading to failure, lack of response, or suboptimal response. Ideally, to bypass genetic resistance, guidelines recommend switching to a second-generation TKI, but for many developing countries, socioeconomic barriers hinder the possibility of switching medication. Despite this scenario, scarce information is available to evaluate the clinical prognosis of these patients. Methods: We conducted a retrospective cohort analysis to compare the overall mortality of patients with CML who developed a suboptimal response to standard-dose imatinib and were treated with either high-dose imatinib or a second-generation TKI. We created a marginal structural model with inverse probability weighting and stabilized weights and depicted the survival curves and median using the Kaplan-Meier estimator. Our primary outcome was overall survival (OS) at 150 months, defined as the number of deaths once patients had reached treatment response based on parameters of the European Leukemia Net Guidelines for CML. Our secondary outcomes were disease-free survival (DFS) at 150 months, defined as the number of months after patients achieved either major molecular response or deep molecular response, and adverse events that included gastrointestinal, dermatologic, hematologic, and others. Results: The cohort included 148 patients, of which 32 received high-dose imatinib and 116 a second-generation TKI. While we found no difference in the 150-month risk in both OS and DFS (Table), patients receiving second-generation TKI had an increase in median survival of OS ( p-value = 0.009). No difference was found in the median survival of DFS ( p-value = 0.55). No difference was found in either hematologic, gastrointestinal, dermatologic, or other adverse events (p-values of 0.39, 0.94, 0.24, and 0.33, respectively). Conclusions: Ideally, patients who develop a suboptimal response to imatinib should be switched to a second-generation TKI. However, If impossible, our findings suggest that patients treated with high-dose imatinib have a similar OS and DFS prognosis to those receiving a second-generation TKI. [Table: see text]
7+3 versus decitabine + venetoclax: A global, propensity-matched study comparing outcomes for both regimens in AML.
Authors: Salimath Varada , Mackey James David , Miles Brittany , Mehta Ankit
Published: June 2024

6537

Background: In the treatment of AML, 7+3 (seven days of standard-dose cytarabine and three days of anthracycline therapy) has long been the standard for attempted remission induction. Recently published studies have explored the efficacy and tolerability of decitabine and venetoclax as a favorable alternative regimen in older adults with AML. However, there has not yet been a head-to-head study in the literature comparing real world outcomes for both regimens. Here we present a retrospective database analysis comparing remission status and mortality among elderly patients treated with 7+3 versus decitabine and venetoclax. Methods: The TriNetX research network was used for this study. Two patient cohorts were created by utilizing International Classification of Disease 10 (ICD-10) codes and medication codes in the TriNetX platform. Both cohorts had patients age 65 and up with a diagnosis of AML (C92.0) and who started treatment within six weeks of diagnosis. The 7+3 cohort received cytarabine and either idarubicin or daunorubicin, while the other cohort received decitabine and venetoclax. Each cohort was excluded from the other treatment to remove crossover as a confounding factor. The cohorts were balanced for age, race, gender, and ethnicity by propensity score matching and the greedy nearest neighbor algorithm. This resulted in 519 patients in each arm. They were then evaluated for the outcome of AML in remission (C92.01) and for death within 12 months. Results: Patients treated with 7+3 were more likely to obtain remission status (54.5% vs 34.7%, RR 1.57, 95% CI (1.36,1.81), P value < 0.0001). The 7+3 cohort also had a lower rate of mortality at 12 months (37% vs 54%, RR 0.69, 95% CI (0.60,0.79), P value < 0.0001). Conclusions: These results show that among elderly patients with AML, treatment with 7+3 is associated with statistically higher remission rates and lower mortality when compared with decitabine and venetoclax therapy. One limitation of our study was that we were not able to determine the cytogenetics in either arm. These results should be taken into consideration when choosing an induction regimen in this population.
Outpatient blinatumomab with digital monitoring in patients with measurable residual disease positive (MRD+) B-ALL in a phase 4 study.
Authors: Pardee Timothy S. , Varela Juan , Jeyakumar Deepa , Keng Michael Kenneth , Bar-Natan Michal , Gundabolu Krishna , Gayle Arlene , McCann Christopher , Xia Qing , Ganzha Sofia , Mergen Noemi , Zaman Faraz , Gordon Paul R. , Khan Sharif S.
Published: June 2024

6544

Background: Blinatumomab, a CD3/CD19-directed BiTE® (bispecific T-cell engager) molecule, is an effective therapy for patients (pts) with MRD+ B-ALL. Hospitalization is recommended for days (D) 1–3 of cycle (C) 1 and D1–2 of C2 for these pts receiving blinatumomab to monitor for serious adverse events (SAEs). This phase 4 study evaluated the safety and feasibility of outpatient (outpt) digital monitoring to replace hospitalization in pts with MRD+ B-ALL (NCT04506086). Methods: Enrolled adults with MRD+ B-ALL in complete remission received continuous intravenous (cIV) blinatumomab at 28 μg/day. Current Health Wearable Monitoring System (CHWMS) was worn by pts at home for D1–3 (C1) and D1–2 (C2), in the presence of a caregiver, and provided heart rate, respiratory rate, and oxygen saturation; a separate patch monitored temperature. Manual blood pressure measurements were taken every 3-6 hrs. Vital signs (VS) were streamed to a provider smartphone/laptop; changes outside a predetermined threshold generated audible alarms. The primary endpoint was incidence of grade (G) ≥3 cytokine release syndrome (CRS), neurotoxicity, or any adverse event (AE) requiring hospitalization during the monitoring period. Results: As of 12/15/2023, 9 pts (median age 43 [20-73] years) received outpt blinatumomab for (completed C1, n=7; C2, n=6). During outpt monitoring, dose interruption was reported in 5 of 9 pts (1 pt had 2 dose interruptions: AE, n=2; dose administration error, n=2; other, n=2). CRS was reported in 2 pts (SAE, n=1; G≥3, n=0; led to interruption, n=1) and neurologic events in 4 pts (SAE, n=0; G≥3, n=0; led to interruption, n=0). Two pts experienced AEs requiring hospitalization (CRS, n=1; fever, n=1). Most VS changes were physiological or from routine pt activity. Median (range) number of alarms triggered/pt was 79 (12-135); among 3 pts, 1.2%, 5.1% and 8.9% of alarms led to therapeutic intervention (Table). Conclusions: To date, outpt administration of cIV blinatumomab in pts with MRD+ B-ALL was feasible and safe with appropriate outpt digital monitoring. Study enrollment is ongoing. Clinical trial information: NCT04506086 . [Table: see text]
TP53 mutation screening for patients at risk of myeloid malignancy.
Authors: Mukherjee Devdeep , Lawal Rialnat A. , Fitzhugh Courtney , Dillon Laura Williams , Hourigan Christopher S.
Published: June 2024

6546

Background: Cellular therapy is a promising approach for many diseases but is associated with a risk of subsequent myelodysplastic syndrome and/or acute myeloid leukemia, also known as therapy-related myeloid neoplasms (tMN). This phenomenon has recently been described with allogeneic hematopoietic cell transplantation (HCT) and gene therapy for sickle cell disease (SCD). Mutation(s) in functional domains of TP53 are often associated with the development of tMN but currently no prospective screening or monitoring technology is available. Methods: A next-generation sequencing (NGS) assay with unique molecular identifiers (UMI) and bioinformatic noise-suppression was designed to discover somatic mutations at a variant allele frequency (VAF) 1% throughout the TP53gene. The background error profile at each base position was calculated using blood genomic DNA from healthy donors. The minimal detectable allele fraction with 95% confidence (MDAF) was calculated for all reported known AML/tMN TP53 hotspots. Orthogonal validation was performed using droplet digital PCR (ddPCR). Results: The median error corrected sequencing depth at 62 known TP53 hotspot regions was 14,512 (95% CI: 14,769 – 15,430) with a theoretical median de novo NGS variant discovery limit of 0.058% (range: 0.037% - 0.13%). Experimental evidence of assay performance characteristics was produced using serial dilutions of 4 missense, 2 splicing, and 1 frameshift TP53 variants with 100% discovery specificity observed (lowest detected VAF range: 0.05 – 0.12%). High correlation was observed in quantification using NGS discovery and ddPCR validation ( r = 0.958, p<0.0001). Pre- and post-HCT clinical samples from 19 patients with SCD, 11 of which had graft failure including 4 who developed tMN, were screened for TP53 mutations. In all tMN cases, the AML-associated TP53 variant was detectable at least 6 months and up to 2.5 years prior to clinical diagnosis of myeloid malignancy. In contrast, no pathogenic TP53 variants were detected in 15 SCD patients who underwent HCT but did not develop tMN. Conclusions: This study provides generalizable evidence that ultra-sensitive discovery of TP53 mutations prior to cellular therapy is possible and could be a potentially valuable clinical tool to screen for tMN risk.
Biomarker testing and adjuvant osimertinib use in patients with resectable EGFR-mutated stage IB–IIIA NSCLC: Physician practices, therapy choice, and barriers among US oncologists.
Authors: Aggarwal Puja , Savill Kristin M. Zimmerman , Jeune-Smith Yolaine , Jennings-Zhang Luke , Bone Robert , Kelly Ronan Joseph , Feinberg Bruce A.
Published: June 2024

e20007

Background: Epidermal Growth Factor Receptor mutations ( EGFRm) are commonly found in patients with resectable and metastatic non-small cell lung cancer (NSCLC). In December 2020, the FDA approved adjuvant osimertinib, for resectable EGFRm NSCLC, based on results of the ADAURA trial which showed significant survival benefit compared to placebo post-resection, further reinforcing need for biomarker testing in NSCLC. In light of publication of Aduara this study aims to understand US oncologists' biomarker testing practices and adjuvant osimertinib use in resectable EGFRm Stage IB–IIIA NSCLC. Methods: Questions related to biomarker testing and adjuvant therapy decision-making for resectable EGFRm Stage IB–IIIA NSCLC were presented to US-based oncologists/hematologists during live meetings in June and July 2023. In addition, questions related to impact of updated overall survival data from ADAURA trial on physicians’ reported treatment preferences were presented.Up to 108 participants responded to questions, though not all participants answered each question. Aggregate responses were summarized using descriptive statistics. Results: Among respondents, 52% identified as medical oncologists and 46% as hematological oncologists, 41% identified as being from an independent community practice and 75% indicated lung cancer was among the 3 solid tumors they most often treat. For patients with newly diagnosed resectable NSCLC patients, respondents indicated that genetic testing was performed before surgery on initial diagnostic biopsy sample (73%), after surgery (44%), and upon progression/relapse (31%). Commonly utilized diagnostic tools reported by respondents included NGS testing of tissue samples (87%), NGS liquid biopsy (42%), and IHC (31%). Barriers impacting molecular testing practices for resectable NSCLC included access to tissue for testing, cost to patient, disease stage, histology, tumor burden, patient age, patient fitness, and prior authorization or time to approval. Half (50%) of respondents reported prescribing adjuvant osimertinib monotherapy for patients with resectable EGFRm NSCLC in the past 6 months. After reviewing the updated ADAURA data, most (83%) respondents indicated they would prescribe adjuvant osimertinib immediately following surgery for resectable EGFRm NSCLC, and 56% would prescribe adjuvant osimertinib with or without adjuvant chemotherapy, 21% would prescribe adjuvant osimertinib with adjuvant chemotherapy, and 17% would prescribe adjuvant osimertinib only. Conclusions: Overall, nearly three-fourths of medical oncologist respondents prefer pre-operative genetic testing and regardless of test timing, when EGFRm identified > 80% will treat adjuvantly with osimertinib. Unfortunately, multiple barriers complicate this pursuit of evidence-based medicine.
Dynamic network biomarker of treg cells differentiation critical state with neoadjuvant treatment in LUSC.
Authors: Meng Yiran , Lin Hai , Zheng Liuqing , Wang Li
Published: June 2024

e20063

Background: Regulatory T cells (Tregs) suppress immune responses and can promote tumor growth and metastasis during cancer progression. Studies have shown that tumor-infiltrating Tregs upregulate inhibitory gene programs after immune checkpoint blockade therapy. Targeting Tregs is believed to be a valuable approach to enhance the effectiveness of immunotherapy. However, the precise role of Tregs in the tumor microenvironment, their connection to treatment resistance mechanisms, and how changes in their immune activity impact tumor treatment are still not well understood. Methods: Single-cell data and clinical information were obtained from the Gene Expression Omnibus database with the accession number GSE176021 for 4 patients diagnosed with lung squamous cell carcinoma (LUSC) who received neoadjuvant anti-PD-1 therapy, including 2 patients with major pathologic response (MPR) and 2 patients with non-MPR. BioTIP was employed to identify critical transition signals of the Treg cell differentiation trajectory constructed by Monocle2. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set variation analysis were performed to understand biological processes and pathways. Additionally, potential transcription factors were identified using Single-Cell rEgulatory Network Inference and Clustering, and CellChat analysis was conducted to evaluate possible interactions among cell populations. Results: The study constructed a pseudo-temporal differentiation trajectory of Tregs in LUSC patients, and Treg subpopulations during the critical transition period were identified based on the dynamic network biomarker method. Notably, subpopulations of Treg cells clustering MPR or non-MPR samples were located at different ends of the differentiation trajectory, showing variations in Treg-related pathways and transcription factor regulation. The critical transition subpopulation exhibited high expression of glycolysis, TCA cycle, and natural killer cell receptors, along with upregulation of the CEBPB transcription factor activity and downregulation of ARNTL activity. SELPLG-SELL, CD99-CD99, and MHC-II-CD4 were identified as potential key signals that may affect therapeutic effect, primarily influencing cell adhesion, the immune suppressive activity of Treg cells, and T cell response. Conclusions: In conclusion, this study utilized single-cell data analysis to uncover the dynamic regulation of Treg cells in LUSC, identifying critical transition Treg subpopulations. Notably, our findings suggest the involvement of the transcription factors CEBPB and ARNTL in regulating Treg activity. These novel insights shed light on potential strategies for targeted therapies and provide valuable information regarding resistance mechanisms associated with Treg cells.
Efficacy and safety of aumolertinib combined with or without chemotherapy as an adjuvant treatment for stage II-IIIA non-small cell lung cancer following complete tumour resection: The first third-generation EGFR-TKI versus chemotherapy phase III clinical study (APEX).
Authors: Tan Feng , Wang Zhijie , Feng Gang , Sun Daqiang , Ma Haitao , Jiang Tao , Wang Sihua , Liu Hongxu , Hu Weidong , Liu Wei , Zhu Yuming , Li Hecheng , Peng Hao , Wu Qingchen , Shen Weiyu , Xu Shun , Zhang Quanren , Han Yongtao , Wang Jie , Gao Shugeng
Published: June 2024

TPS8117

Background: Patients with stage II-III A non-small cell lung cancer (NSCLC) can benefit from adjuvant targeted therapy. ADAURA study shows a remarkable advantage of disease-free survival (DFS). However, there are still unresolved clinical issues. Firstly, the control group in the trial is received placebo, making it impossible to directly compare the efficacy of adjuvant targeted therapy with the traditionally recommended adjuvant chemotherapy in guidelines. Thus, it cannot address the direct comparison of third-generation TKIs with the current standard therapy (chemotherapy). Secondly, the necessity of combining chemotherapy with adjuvant targeted therapy need to explored. Aumolertinib is a third-generation epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR sensitizing and EGFR T790M resistance mutations. This study aims to evaluate the efficacy and safety of aumolertinib combined with or without chemotherapy as adjuvant treatment for EGFR-sensitive mutations stage II-III A non-squamous NSCLC patients. Methods: This is a multicenter, randomized, open label, phase III study. Patients with histologically confirmed stage II-III A non-squamous NSCLC harboring EGFR mutations without prior EGFR TKI treatment and R0 resection are eligible for this study. The performance status (Eastern Cooperative Oncology Group) is 0 or 1. This trial prepared to enroll approximately 606 patients, will be randomized (3:2:1) to receive either aumolertinib alone (110mg, po, once daily) or aumolertinib (110mg, po, once daily) plus pemetrexed (500mg/m2, iv) and cisplatin (500mg/m2, iv) or pemetrexed (500mg/m2, iv) plus cisplatin (500mg/m2, iv). The first patient was enrolled on August 2, 2021. The primary end point is DFS, The secondary endpoints include 2, 3, 4, 5-year DFS rates, 5-year overall survival (OS), OS, safety and quality of life. Adverse effects were graded per CTCAE v.4.0. This trial is registered as NCT04762459. Clinical trial information: NCT04762459 .
Cardiorespiratory Fitness, Body Composition, Diabetes, and Longevity: A 2-Sample Mendelian Randomization Study
Authors: Kjaergaard Alisa D , Ellervik Christina , Jessen Niels , Lessard Sarah J
Published: June 2024

Context

Cardiorespiratory fitness, commonly assessed as maximal volume of oxygen consumption (VO2max), has emerged as an important predictor of morbidity and mortality.

Objective

We investigated the causality and directionality of the associations of VO2max with body composition, physical activity, diabetes, performance enhancers, and longevity.

Methods

Using publicly available summary statistics from the largest genome-wide association studies publicly available, we conducted a bidirectional 2-sample Mendelian randomization (MR) study. Bidirectional MR tested directionality, and estimated the total causal effects, whereas multivariable MR (MVMR) estimated independent causal effects. Cardiorespiratory fitness (VO2max) was estimated from a submaximal cycle ramp test (N ≈ 70 000) and scaled to total body weight, and in additional analyses to fat-free mass (mL/min/kg).

Results

Genetically predicted higher (per 1 SD increase) body fat percentage was associated with lower VO2max (β = −0.36; 95% CI: −0.40, −0.32, P = 6 × 10–77). Meanwhile, genetically predicted higher appendicular lean mass (β = 0.10; 95% CI: 0.08 to 0.13), physical activity (β = 0.29; 95% CI: 0.07 to 0.52), and performance enhancers (fasting insulin, hematocrit, and free testosterone in men) were all positively associated with VO2max (all P < .01). Genetic predisposition to diabetes had no effect on VO2max. MVMR showed independent causal effects of body fat percentage, appendicular lean mass, physical activity, and hematocrit on VO2max, as well as of body fat percentage and type 2 diabetes (T2D) on longevity. Genetically predicted VO2max showed no associations.

Conclusion

Cardiorespiratory fitness can be improved by favorable body composition, physical activity, and performance enhancers. Despite being a strong predictor of mortality, VO2max is not causally associated with T2D or longevity.
The Impact of Adverse Pregnancy Events in the Initial Cycle on Subsequent Pregnancy Outcomes
Authors: Xu Qiuyu , Mao Xiaoyan , Zhang Jie , Chen Yan , Wu Ling
Published: June 2024

Context

Evidence is accumulating on the impact of previous adverse pregnancy events on future fertility in natural conceptions. However, there is limited knowledge on whether an ectopic pregnancy (EP) or miscarriage after an initial in vitro fertilization (IVF) cycle affects the subsequent outcomes.

Objective

To investigate the effect of first IVF outcomes (miscarriage, EP, and no pregnancy) on second cycle outcomes based on a freeze-all strategy.

Methods

Retrospective cohort study at a university-affiliated IVF center. This study involved 16 479 women who had undergone 2 complete frozen embryo transfers (FETs) and who were classified into 3 groups based on first FET outcomes. The main outcome measure was live birth rate (LBR).

Results

After correcting for confounders, the LBR after the second FET was similar between women who suffered an EP and those who had no pregnancies in their first FET cycles (adjusted odds ratio [aOR] 1.03; 95% CI 0.83-1.28). However, women who experienced a miscarriage vs those with no prior pregnancy in the first FET had significantly higher LBR in their second cycles (aOR 1.33; 95% CI 1.20-1.48). The LBR after the second FET was similar between the previous EP and miscarriage groups (aOR 1.24; 95% CI 0.98-1.58). Similar results were found in propensity score matching models, supporting the robustness of the main findings.

Conclusion

Women who had a miscarriage in the first FET cycle had a higher chance of achieving live births in the subsequent treatment cycle than those who had no pregnancy in the initial cycle. Furthermore, it was found that an EP resulting from the first treatment cycle did not negatively impact reproductive outcomes in the next FET cycles.
Diagnostic Accuracy of Transient Elastography in Hepatosteatosis in Youth With Obesity
Authors: Tas Emir , Sundararajan Divya , Lo Jaclyn S , Morelli Nazeen , Garcia-Reyes Yesenia , Ware Meredith A , Rahat Haseeb , Ou Xiawei , Na Xiaoxu , Sundaram Shikha , Severn Cameron , Pyle Laura L , Børsheim Elisabet , Vajravelu Mary Ellen , Muzumdar Radhika , Dranoff Jonathan A , Cree Melanie G
Published: June 2024

Context

Steatotic liver disease is common but overlooked in childhood obesity; diagnostic methods are invasive or expensive.

Objective

We sought to determine the diagnostic accuracy of vibration-controlled transient elastography (VCTE) compared with magnetic resonance imaging (MRI) in adolescents with obesity and high risk for hepatosteatosis.

Methods

Baseline data in 3 clinical trials enrolling adolescents with obesity were included (NCT03919929, NCT03717935, NCT04342390). Liver fat was assessed using MRI fat fraction and VCTE-based controlled attenuation parameter (CAP). Hepatosteatosis was defined as MRI fat fraction ≥5.0%. The area under the receiver-operating characteristic curves (AUROCs) for CAP against MRI was calculated, and optimal CAP using the Youden index for hepatosteatosis diagnosis was determined.

Results

Data from 82 adolescents (age 15.6 ± 1.4 years, body mass index 36.5 ± 5.9 kg/m2, 81% female) were included. Fifty youth had hepatosteatosis by MRI (fat fraction 9.3% ; 95% CI 6.7, 14.0), and 32 participants did not have hepatosteatosis (fat fraction 3.1%; 95% CI 2.2, 3.9; P < .001). The hepatosteatosis group had higher mean CAP compared with no hepatosteatosis (293 dB/m; 95% CI 267, 325 vs 267 dB/m; 95% CI 248, 282; P = .0120). A CAP of 281 dB/m had the highest sensitivity (60%) and specificity (74%) with AUROC of 0.649 (95% CI 0.51-0.79; P = .04) in the entire cohort. In a subset of participants with polycystic ovary syndrome (PCOS), a CAP of 306 dB/m had the highest sensitivity (78%) and specificity (52%) and AUROC of 0.678 (95% CI 0.45-0.90; P = .108).

Conclusion

CAP of 281 dB/m has modest diagnostic performance for hepatosteatosis compared with MRI in youth with significant obesity. A higher CAP in youth with PCOS suggests that comorbidities might affect optimal CAP in hepatosteatosis diagnosis.
Cerebellar granular neuron progenitors exit their germinative niche via BarH-like1 activity mediated partly by inhibition of T-cell factor
Authors: Bou-Rouphael Johnny , Doulazmi Mohamed , Eschstruth Alexis , Abdou Asna , Durand Béatrice C.
Published: June 2024

Cerebellar granule neuron progenitors (GNPs) originate from the upper rhombic lip (URL), a germinative niche in which developmental defects produce human diseases. T-cell factor (TCF) responsiveness and Notch dependence are hallmarks of self-renewal in neural stem cells. TCF activity, together with transcripts encoding proneural gene repressors hairy and enhancer of split (Hes/Hey), are detected in the URL; however, their functions and regulatory modes are undeciphered. Here, we established amphibian as a pertinent model for studying vertebrate URL development. The amphibian long-lived URL is TCF active, whereas the external granular layer (EGL) is non-proliferative and expresses hes4 and hes5 genes. Using functional and transcriptomic approaches, we show that TCF activity is necessary for URL emergence and maintenance. We establish that the transcription factor Barhl1 controls GNP exit from the URL, acting partly through direct TCF inhibition. Identification of Barhl1 target genes suggests that, besides TCF, Barhl1 inhibits transcription of hes5 genes independently of Notch signaling. Observations in amniotes suggest a conserved role for Barhl in maintenance of the URL and/or EGL via co-regulation of TCF, Hes and Hey genes.