bluuebunny/crossref_metadata_2025 huggingface dataset:
Financial incentives to motivate treatment for hepatitis C with direct acting antivirals among Australian adults (The Methodical evaluation and Optimisation of Targeted IncentiVes for Accessing Treatment of Early-stage hepatitis C: MOTIVATE-C): protocol for a dose-response randomised controlled study
Authors: Fathima Parveen , Jones Mark , D’Souza Reena , Totterdell James , Andric Nada , Abbott Penelope , Norman Richard , Howard Kirsten , Cheng Wendy , Pedrana Alisa , Doyle Joseph S. , Davies Jane , Snelling Thomas
Published: June 2024

Background

Untreated hepatitis C virus (HCV) infection can result in cirrhosis and hepatocellular cancer. Direct-acting antiviral (DAA) therapies are highly effective and have few side effects compared to older interferon-based therapy. Despite the Australian government providing subsidised and unrestricted access to DAA therapy for chronic HCV infection, uptake has not been sufficient to meet the global target of eliminating HCV as a public health threat by 2030. This study will offer people with HCV financial incentives of varying values in order to evaluate its effect on initiation of DAA therapy in primary care.

Methods

Australian adults (18 years or older) who self-report as having current untreated HCV infection can register to participate via an automated SMS-based system. Following self-screening for eligibility, registrants are offered a financial incentive of randomised value (AUD 0 to 1000) to initiate DAA therapy. Study treatment navigators contact registrants who have consented to be contacted, to complete eligibility assessment, outline the study procedures (including the requirement for participants to consult a primary care provider), obtain consent, and finalise enrolment. Enrolled participants receive their offered incentive on provision of evidence of DAA therapy initiation within 12 weeks of registration (primary endpoint). Balanced randomisation is used across the incentive range until the first analysis, after which response-adaptive randomisation will be used to update the assignment probabilities. For the primary analysis, a Bayesian 4-parameter EMAX model will be used to estimate the dose–response curve and contrast treatment initiation at each incentive value against the control arm (AUD 0). Specified secondary statistical and economic analyses will evaluate the effect of incentives on adherence to DAA therapy, virological response, and cost-effectiveness.

Discussion

This project seeks to gain an understanding of the dose–response relationship between incentive value and DAA treatment initiation, while maximising the number of people treated for HCV within fixed budget and time constraints. In doing so, we hope to offer policy-relevant recommendation(s) for the use of financial incentives as a pragmatic, efficient, and cost-effective approach to achieving elimination of HCV from Australia.

Trial registration

ANZCTR (anzctr.org.au), Identifier ACTRN12623000024640, Registered 11 January 2023 (https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384923&isReview=true).
CRISPR-Cas9 screens reveal common essential miRNAs in human cancer cell lines
Authors: Merk Daniel J. , Paul Linda , Tsiami Foteini , Hohenthanner Helen , Kouchesfahani Ghazal Mohseni , Haeusser Lara A. , Walter Bianca , Brown Adam , Persky Nicole S. , Root David E. , Tabatabai Ghazaleh
Published: June 2024

Background

Genome-wide functional screening using the CRISPR-Cas9 system is a powerful tool to uncover tumor-specific and common genetic dependencies across cancer cell lines. Current CRISPR-Cas9 knockout libraries, however, primarily target protein-coding genes. This limits functional genomics-based investigations of miRNA function.

Methods

We designed a novel CRISPR-Cas9 knockout library (lentiG-miR) of 8107 distinct sgRNAs targeting a total of 1769 human miRNAs and benchmarked its single guide RNA (sgRNA) composition, predicted on- and off-target activity, and screening performance against previous libraries. Using a total of 45 human cancer cell lines, representing 16 different tumor entities, we performed negative selection screens to identify miRNA fitness genes. Fitness miRNAs in each cell line were scored using a combination of supervised and unsupervised essentiality classifiers. Common essential miRNAs across distinct cancer cell lines were determined using the 90th percentile method. For subsequent validation, we performed knockout experiments for selected common essential miRNAs in distinct cancer cell lines and gene expression profiling.

Results

We found significantly lower off-target activity for protein-coding genes and a higher miRNA gene coverage for lentiG-miR as compared to previously described miRNA-targeting libraries, while preserving high on-target activity. A minor fraction of miRNAs displayed robust depletion of targeting sgRNAs, and we observed a high level of consistency between redundant sgRNAs targeting the same miRNA gene. Across 45 human cancer cell lines, only 217 (12%) of all targeted human miRNAs scored as a fitness gene in at least one model, and fitness effects for most miRNAs were confined to small subsets of cell lines. In contrast, we identified 49 common essential miRNAs with a homogenous fitness profile across the vast majority of all cell lines. Transcriptional profiling verified highly consistent gene expression changes in response to knockout of individual common essential miRNAs across a diverse set of cancer cell lines.

Conclusions

Our study presents a miRNA-targeting CRISPR-Cas9 knockout library with high gene coverage and optimized on- and off-target activities. Taking advantage of the lentiG-miR library, we define a catalogue of miRNA fitness genes in human cancer cell lines, providing the foundation for further investigation of miRNAs in human cancer.
Porcine deltacoronavirus nonstructural protein 2 inhibits type I and III IFN production by targeting STING for degradation
Authors: Liu Xiqian , Ji Likai , Cheng Yuqiang , Kong Linghe , Xie Songhua , Yang Juan , Chen Jiaqi , Wang Zhaofei , Ma Jingjiao , Wang Hengan , Yan Yaxian , Sun Jianhe
Published: June 2024

Porcine deltacoronavirus (PDCoV) is an enteropathogenic coronavirus that has been reported to use various strategies to counter the host antiviral innate immune response. The cGAS-STING signalling pathway plays an important role in antiviral innate immunity. However, it remains unclear whether PDCoV achieves immune evasion by regulating the cGAS-STING pathway. Here, we demonstrated that the nonstructural protein 2 (nsp2) encoded by PDCoV inhibits cGAS-STING-mediated type I and III interferon (IFN) responses via the regulation of porcine STING (pSTING) stability. Mechanistically, ectopically expressed PDCoV nsp2 was found to interact with the N-terminal region of pSTING. Consequently, pSTING was degraded through K48-linked ubiquitination and the proteasomal pathway, leading to the disruption of cGAS-STING signalling. Furthermore, K150 and K236 of pSTING were identified as crucial residues for nsp2-mediated ubiquitination and degradation. In summary, our findings provide a basis for elucidating the immune evasion mechanism of PDCoV and will contribute to the development of targets for anti-coronavirus drugs.
Families’ importance in nursing care–families’ opinions: a cross-sectional survey study in the homecare setting
Authors: Woldring Josien M. , Paans Wolter , Gans Reinold , Dorland Laura , Luttik Marie Louise
Published: June 2024

Background

Informal care is an essential part of support provided in the homecare setting. To ensure effective healthcare provision, good communication and collaboration between informal and formal care providers are crucial. To achieve this aim, it is necessary to have a clear understanding of the perspectives of all stakeholders. In the scientific literature, limited knowledge is available regarding family members’ opinions about their involvement in care. To date, no instruments have been developed that accurately measure these opinions. This study aims to elucidate the opinions of family members about their involvement in nursing care.

Methods

A cross-sectional survey approach was employed. The methodological steps in this study were (1) convert the Families’ Importance in Nursing Care–Nurses’ Attitudes (FINC-NA) from a nurses’ perspective to a family perspective and thus develop the Families’ Importance in Nursing Care–Families’ Opinions (FINC-FO) and (2) measure families’ opinions regarding their involvement in home nursing care. The questionnaire was sent to 3,800 patients with activated patient portals, which accounts for about 17% of the total patient base. Responses were received from 1,339 family members, a response rate of 35%.

Results

The developed FINC-FO questionnaire showed homogeneity and internal consistency. The results of the questionnaire indicate that family members consider it important to be involved in care and that they wish to be acknowledged as participants in discussions about care (planning) but are less inclined to actively participate in the provision of care by nurses. Family members expressed less explicit opinions about their own support needs. Factors such as level of education, type of partnership, and amount of care provided are seemingly associated with these opinions.

Conclusions

Family members in the homecare setting wish to be involved in discussions about care (planning). The transition in care from primarily formal to more informal care necessitates an awareness and clear definition—on part of both healthcare professionals and families—of their respective roles in the provision of care. Communication about wishes, expectations, and the need for support in care is essential to ensure quality of care and that the family can sustain caregiving.
Hemostatic effects of tranexamic acid in cardiac surgical patients with antiplatelet therapy: a systematic review and meta-analysis
Authors: Tian Lijuan , Li Xiaotao , He Lixian , Ji Hongwen , Yao Yuntai ,   the Evidence in Cardiovascular Anesthesia (EICA) Group
Published: June 2024

Background

The purpose of the current study was to assess the efficacy of tranexamic acid (TXA) on reducing bleeding in cardiac surgical patients with preoperative antiplatelet therapy (APT).

Methods

Five electronic databases were searched systematically for randomized-controlled trials (RCTs) assessing the impact of intravenous TXA on post-operative bleeding on cardiac surgical patients with preoperative APT until May 2024. Primary outcome of interest was post-operative blood loss. Secondary outcomes of interest included the incidence of reoperation due to post-operative bleeding, post-operative transfusion requirements of red blood cells (RBC), fresh-frozen plasma (FFP), and platelet concentrates. Mean difference (MD) with 95% confidence interval (CI) or odds ratios (OR) with 95% CI was employed to analyze the data. Subgroup and meta-regression analyses were performed to assess the possible influence of TXA administration on reducing bleeding and transfusion requirements.

Results

A total of 12 RCTs with 3018 adult cardiac surgical patients (TXA group, 1510 patients; Control group, 1508 patients) were included. The current study demonstrated that TXA significantly reduced post-operative blood loss (MD =  − 0.38 L, 95% CI: − 0.73 to − 0.03, P = 0.03; MD =  − 0.26 L, 95% CI: − 0.28 to − 0.24, P < 0.00001; MD =  − 0.37 L, 95% CI: − 0.63 to − 0.10, P = 0.007) in patients receiving dual antiplatelet therapy (DAPT), aspirin, or clopidogrel, respectively. Patients in TXA group had significantly lower incidence of reoperation for bleeding as compared to those in Control group. The post-operative transfusion of RBC and FFP requirements was significantly lower in TXA group than Control group. Subgroup analyses showed that studies with DAPT discontinued on the day of surgery significantly increased the risk of post-operative blood loss [(MD: − 1.23 L; 95% CI: − 1.42 to − 1.04) vs. (MD: − 0.16 L; 95% CI: − 0.27 to − 0.05); P < 0.00001 for subgroup difference] and RBC transfusion [(MD: − 3.90 units; 95% CI: − 4.75 to − 3.05) vs. (MD: − 1.03 units; 95% CI: − 1.96 to − 0.10); P < 0.00001 for subgroup difference] than those with DAPT discontinued less than 5–7 days preoperatively.

Conclusions

This meta-analysis demonstrated that TXA significantly reduced post-operative blood loss and transfusion requirements for cardiac surgical patients with preoperative APT. These potential clinical benefits may be greater in patients with aspirin and clopidogrel continued closer to the day of surgery.

Trial registration number

CRD42022309427.
Measurement invariance of the Pandemic Anxiety Inventory in different demographic groups
Authors: Schonfeld Irvin Sam , Prytherch Tasmyn , Cropley Mark , Verkuilen Jay , Bianchi Renzo
Published: June 2024

Background

The Pandemic Anxiety Inventory (PAI) was developed in the context of the COVID-19 pandemic. Its content allows it to assess anxiety in connection to any pandemic. Previous research has demonstrated the instrument’s reliability and validity. An important question for clinicians and researchers, however, remains open: Does the PAI have similar meaning for members of different demographic groups? The finding of measurement invariance would allow clinicians and researchers to comparatively assess pandemic-related anxiety across demographic groups, including favored and disfavored groups.

Methods

We conducted a multi-group confirmatory factor analysis to assess the measurement invariance of the PAI using data obtained from a sample of 379 residents of the United Kingdom.

Results

The PAI demonstrated invariance across genders, age groups, individuals who are married or in a relationship and those who are not, as well as individuals with higher and lower incomes. In an ancillary analysis, we found invariance across subsamples of Whites and Nonwhites, although we note that the Nonwhite group was small (n = 60) and heterogeneous. The findings of a supplemental MIMIC analysis were consistent with the above.

Conclusions

The PAI shows measurement invariance across a variety of demographic groups. Our findings suggest that the instrument can be meaningfully employed to compare pandemic-related anxiety across these groups.
Original or post-war paintings? The fixed wooden scenery of the Teatro Olimpico in Vicenza: a guided multidisciplinary approach based on scientific analyses and HBIM
Authors: Antonelli Fabrizio , Piovesan Rebecca , Tesser Elena , Tosato Marco , Sorbo Emanuela
Published: June 2024

Archival resources, a photogrammetric survey, analysis of materials and techniques, and evaluation of the state of conservation were interconnected phases in the interdisciplinary research on the perspective scenery of the Teatro Olimpico in Vicenza. To fill existing gaps related to the history of this unique artefact and to the undocumented retouching of paint layers on the scenery during post-war reconstruction work, a broad analytical approach (optical microscopy, XRPD, SEM–EDX, μFTIR and μRaman) was applied to micro-samples, the selection of which was guided by consolidated geometrical and archival data. The aims were to obtain a characterisation of the pigments and binders and to evaluate the microstratigraphic sequence, the state of conservation of the scenery flats, and the deterioration processes involved. The findings unveiled a discernible variability in the production techniques of the finishes, frequently lacking the classic microstratigraphic sequence associated with the traditional method for painting on wooden panels from the sixteenth century. Moreover, by identifying many pigments that could be used as temporal markers we were able unequivocally to establish, for the first time, that a significant part of the scenery designed by the architect Vincenzo Scamozzi was heavily repainted in the post-WWII period. These analytical results and all the data collected on the artefacts over time were related through an HBIM model, enabling the historical and technical-analytical information to be linked to the geometrical survey and thus to provide guidance for actions based on current and future knowledge for the maintenance and monitoring of the Teatro Olimpico.
Data oversampling and imbalanced datasets: an investigation of performance for machine learning and feature engineering
Authors: Mujahid Muhammad , Kına EROL , Rustam Furqan , Villar Monica Gracia , Alvarado Eduardo Silva , De La Torre Diez Isabel , Ashraf Imran
Published: June 2024

The classification of imbalanced datasets is a prominent task in text mining and machine learning. The number of samples in each class is not uniformly distributed; one class contains a large number of samples while the other has a small number. Overfitting of the model occurs as a result of imbalanced datasets, resulting in poor performance. In this study, we compare different oversampling techniques like synthetic minority oversampling technique (SMOTE), support vector machine SMOTE (SVM-SMOTE), Border-line SMOTE, K-means SMOTE, and adaptive synthetic (ADASYN) oversampling to address the issue of imbalanced datasets and enhance the performance of machine learning models. Preprocessing significantly enhances the quality of input data by reducing noise, redundant data, and unnecessary data. This enables the machines to identify crucial patterns that facilitate the extraction of significant and pertinent information from the preprocessed data. This study preprocesses the data using various top-level preprocessing steps. Furthermore, two imbalanced Twitter datasets are used to compare the performance of oversampling techniques with six machine learning models including random forest (RF), SVM, K-nearest neighbor (KNN), AdaBoost (ADA), logistic regression (LR), and decision tree (DT). In addition, the bag of words (BoW) and term frequency and inverse document frequency (TF-IDF) features extraction approaches are used to extract features from the tweets. The experiments indicate that SMOTE and ADASYN perform much better than other techniques thus providing higher accuracy. Additionally, overall results show that SVM with ’linear’ kernel tends to attain the highest accuracy and recall score of 99.67% and 1.00% on ADASYN oversampled datasets and 99.57% accuracy on SMOTE oversampled dataset with TF-IDF features. The SVM model using 10-fold cross-validation experiments achieved 97.40 mean accuracy with a 0.008 standard deviation. Our approach achieved 2.62% greater accuracy as compared to other current methods.
Green biosynthesis of bimetallic ZnO@AuNPs with its formulation into cellulose derivative: biological and environmental applications
Authors: Al Abboud Mohamed A. , Mashraqi Abdullah , Qanash Husam , Gattan Hattan S. , Felemban Hashim R. , Alkorbi Faeza , Alawlaqi Mohamed M. , Abdelghany Tarek M. , Moawad Hanan
Published: June 2024

Nanoparticles (NPs) formulation in biopolymers is an attractive process for the researcher to decrease the disadvantages of NPs application alone. Bimetallic NPs are a promising formula of two NPs that usually act as synergetic phenomena. Zinc oxide and gold NPs (ZnO@AuNPs) biosynthesis as a bimetallic was prepared via the eco-friendly manner currently. Carboxymethylcellulose (CMC) was employed for the formulation of ZnO@AuNPs as a nanocomposite via a green method. Physicochemical and topographical characterization was assigned to ZnO@AuNPs and nanocomposite features. The nanostructure of bimetallic NPs and nanocomposite were affirmed with sizes around 15 and 25 nm, respectively. Indeed, the DLS measurements affirmed the more reasonable size and stability of the prepared samples as 27 and 93 nm for bimetallic NPs and nanocomposite, respectively. The inhibitory potential of nanocomposite was more than ZnO@AuNPs against Staphylococcus aureus, Escherichia coli, Salmonella typhi, Enterococcus faecalis, Mucor albicans, Aspergillus flavus, and Mucor circinelloid. ZnO@AuNPs and nanocomposite exhibited antioxidant activity via DPPH with IC50 of 71.38 and 32.4 µg/mL, correspondingly. Excellent anti-diabetic potential of nanocomposite with IC50 of 7.4 µg/mL, and ZnO@AuNPs with IC50 of 9.7 µg/mL was reported compared with the standard acarbose with the IC50 of 50.93 µg/mL for amylase inhibition (%). Photocatalytic degradation of RR195 and RB dyes was performed by ZnO@AuNPs and nanocomposite, where maximum degradation was 85.7 ± 1.53 and 88.7 ± 0.58%, respectively using ZnO@AuNPs, 90.3 ± 0.28 and 91.8 ± 0.27%, respectively using nanocomposite at 100 min.

Graphical Abstract
Self-selection or situational stratification? A quasiexperimental study on social class differences in health behaviors in China
Authors: Hong Yanbi , Zeng Diyang , Shen Ji
Published: June 2024

Fundamental cause theory suggests that differences in social status lead to health inequalities, with lifestyle serving as the intermediary mechanism. This study uses multiple waves of data from the China Family Panel Studies (CFPS) to first explore differences in drinking, smoking, and physical exercise across different social classes and finds that managers have significantly greater tendencies toward risky health behaviors such as drinking and smoking. Subsequently, the study examines changes in class differences in drinking behavior with respect to the anticorruption policy. The results show that neither lifestyle transition theory nor the self-selection mechanism can fully explain the phenomenon of managers drinking more. Health stratification is not a simple reflection of the socioeconomic status gradient, and there is an urgent need to rethink the theoretical framework of social stratification that emphasizes microlevel individual practices as a direct reflection of macrostructural positions.
Determining the footprint of breeding in the seed microbiome of a perennial cereal
Authors: Michl Kristina , David Christophe , Dumont Benjamin , Mårtensson Linda-Maria Dimitrova , Rasche Frank , Berg Gabriele , Cernava Tomislav
Published: June 2024

Background

Seed endophytes have a significant impact on plant health and fitness. They can be inherited and passed on to the next plant generation. However, the impact of breeding on their composition in seeds is less understood. Here, we studied the indigenous seed microbiome of a recently domesticated perennial grain crop (Intermediate wheatgrass, Thinopyrum intermedium L.) that promises great potential for harnessing microorganisms to enhance crop performance by a multiphasic approach, including amplicon and strain libraries, as well as molecular and physiological assays.

Results

Intermediate wheatgrass seeds harvested from four field sites in Europe over three consecutive years were dominated by Proteobacteria (88%), followed by Firmicutes (10%). Pantoea was the most abundant genus and Pantoea agglomerans was identified as the only core taxon present in all samples. While bacterial diversity and species richness were similar across all accessions, the relative abundance varied especially in terms of low abundant and rare taxa. Seeds from four different breeding cycles (TLI C3, C5, C704, C801) showed significant differences in bacterial community composition and abundance. We found a decrease in the relative abundance of the functional genes nirK and nifH as well as a drop in bacterial diversity and richness. This was associated with a loss of amplicon sequence variants (ASVs) in Actinobacteria, Alphaproteobacteria, and Bacilli, which could be partially compensated in offspring seeds, which have been cultivated at a new site. Interestingly, only a subset assigned to potentially beneficial bacteria, e.g. Pantoea, Kosakonia, and Pseudomonas, was transmitted to the next plant generation or shared with offspring seeds.

Conclusion

Overall, this study advances our understanding of the assembly and transmission of endophytic seed microorganisms in perennial intermediate wheatgrass and highlights the importance of considering the plant microbiome in future breeding programs.
CT and MRI radiomic features of lung cancer (NSCLC): comparison and software consistency
Authors: Bortolotto Chandra , Pinto Alessandra , Brero Francesca , Messana Gaia , Cabini Raffaella Fiamma , Postuma Ian , Robustelli Test Agnese , Stella Giulia Maria , Galli Giulia , Mariani Manuel , Figini Silvia , Lascialfari Alessandro , Filippi Andrea Riccardo , Bottinelli Olivia Maria , Preda Lorenzo
Published: June 2024

Background

Radiomics is a quantitative approach that allows the extraction of mineable data from medical images. Despite the growing clinical interest, radiomics studies are affected by variability stemming from analysis choices. We aimed to investigate the agreement between two open-source radiomics software for both contrast-enhanced computed tomography (CT) and contrast-enhanced magnetic resonance imaging (MRI) of lung cancers and to preliminarily evaluate the existence of radiomic features stable for both techniques.

Methods

Contrast-enhanced CT and MRI images of 35 patients affected with non-small cell lung cancer (NSCLC) were manually segmented and preprocessed using three different methods. Sixty-six Image Biomarker Standardisation Initiative-compliant features common to the considered platforms, PyRadiomics and LIFEx, were extracted. The correlation among features with the same mathematical definition was analyzed by comparing PyRadiomics and LIFEx (at fixed imaging technique), and MRI with CT results (for the same software).

Results

When assessing the agreement between LIFEx and PyRadiomics across the considered resampling, the maximum statistically significant correlations were observed to be 94% for CT features and 95% for MRI ones. When examining the correlation between features extracted from contrast-enhanced CT and MRI using the same software, higher significant correspondences were identified in 11% of features for both software.

Conclusions

Considering NSCLC, (i) for both imaging techniques, LIFEx and PyRadiomics agreed on average for 90% of features, with MRI being more affected by resampling and (ii) CT and MRI contained mostly non-redundant information, but there are shape features and, more importantly, texture features that can be singled out by both techniques.

Relevance statement

Identifying and selecting features that are stable cross-modalities may be one of the strategies to pave the way for radiomics clinical translation.

Key points

• More than 90% of LIFEx and PyRadiomics features contain the same information.

• Ten percent of features (shape, texture) are stable among contrast-enhanced CT and MRI.

• Software compliance and cross-modalities stability features are impacted by the resampling method.

Graphical Abstract
Two-step hierarchical binary classification of cancerous skin lesions using transfer learning and the random forest algorithm
Authors: Suleiman Taofik Ahmed , Anyimadu Daniel Tweneboah , Permana Andrew Dwi , Ngim Hsham Abdalgny Abdalwhab , Scotto di Freca Alessandra
Published: June 2024

Skin lesion classification plays a crucial role in the early detection and diagnosis of various skin conditions. Recent advances in computer-aided diagnostic techniques have been instrumental in timely intervention, thereby improving patient outcomes, particularly in rural communities lacking specialized expertise. Despite the widespread adoption of convolutional neural networks (CNNs) in skin disease detection, their effectiveness has been hindered by the limited size and data imbalance of publicly accessible skin lesion datasets. In this context, a two-step hierarchical binary classification approach is proposed utilizing hybrid machine and deep learning (DL) techniques. Experiments conducted on the International Skin Imaging Collaboration (ISIC 2017) dataset demonstrate the effectiveness of the hierarchical approach in handling large class imbalances. Specifically, employing DenseNet121 (DNET) as a feature extractor and random forest (RF) as a classifier yielded the most promising results, achieving a balanced multiclass accuracy (BMA) of 91.07% compared to the pure deep-learning model (end-to-end DNET) with a BMA of 88.66%. The RF ensemble exhibited significantly greater efficiency than other machine-learning classifiers in aiding DL to address the challenge of learning with limited data. Furthermore, the implemented predictive hybrid hierarchical model demonstrated enhanced performance while significantly reducing computational time, indicating its potential efficiency in real-world applications for the classification of skin lesions.
Evaluating circulating cell-free DNA and DNA integrity index as biomarkers in non-small cell lung cancer
Authors: Ezzeldin Nada , El-Lebedy Dalia , Hassan Mirhane , Shalaby Alaa Omar , Hussein Sabah Ahmed Mohamed , Gharib Ahmed Mohamed , Hamdy Gehan , Mohammed Asmaa Mahmoud , Ramadan Abeer , Sobeih Mohamed Emam
Published: June 2024

Background

Analysis of free DNA molecules shed from tumour cells in plasma of patients referred as circulating tumour DNA (ctDNA) with reference to physiological circulating cell-free DNA (cfDNA) is nowadays exploited as liquid biopsy and is considered a new emerging promising biomarker for diagnosis, selection of proper treatment, and prognosis of cancer. DNA integrity index (DII) is assessed by calculating the ratio between the concentration of long cfDNA strands released from tumour cells (ALU247) and the short strands released from normal cells (ALU115). The aim of the current study was to evaluate DII as a potential diagnostic and prognostic biomarker of NSCLC.

Methods

Our study included 48 NSCLC patients diagnosed as primary NSCLC before starting treatment, 30 COPD patients diagnosed clinically, radiologically, and subjected to chest high-resolution computerized tomography, and 40 healthy controls. cfDNA concentration and DII were measured by quantitative real-time polymerase chain reaction (qPCR).

Results

ALU115, ALU247, and DII were significantly higher in NSCLC compared to COPD patients (p < 0.0001) and controls (p < 0.0001) and in COPD patients compared to control subjects (p < 0.0001). DII positively correlated with the stage of tumour (p = 0.01), tumour metastasis (p = 0.004), and with adenocarcinoma compared to other histopathological types (p = 0.02). To evaluate clinical utility of DII in NSCLC, ROC curve analysis demonstrated an AUC of 0.91 at a cut-off value of 0.44 with total accuracy = 85.6%, sensitivity = 90%, specificity = 83%, PPV = 78.1%, and NPV = 92.1%.

Conclusion

cfDNA and DII represent a promising diagnostic and prognostic tool in NSCLC. This type of noninvasive liquid biopsy revealed its chance in the screening, early diagnosis, and monitoring of NSCLC.
Comparative diagnostic performance of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) versus endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) for tissue sampling of solid pancreatic and non-pancreatic lesions without ROSE: a prospective multicenter study
Authors: Okasha Hussein Hassan , Ahmed Mohammed Yousri , Ahmed Marwa A. , Elenin Sameh Abou , Abdel-latif Abeer , Farouk Mahmoud , Ameen Mahmoud Gamal , El-Habashi Ahmed Hussein , Elshaer Mahasen Akram , Alzamzamy Ahmed Elsayed
Published: June 2024

Background and aims

Endoscopic ultrasound-guided tissue acquisition, including both fine-needle aspiration (EUS-FNA) and fine-needle biopsy (EUS-FNB), has been frequently performed to acquire samples from both pancreatic and non-pancreatic lesions. Still, the impact of the diagnostic yield between FNA and FNB is uncertain. We conducted this study to compare the diagnostic performance and accuracy of the 22-gauge FNA needles with the 22-gauge FNB needles in sampling solid pancreatic and non-pancreatic lesions.

Methods

This is a prospective multicenter study conducted on 465 cases presented with solid pancreatic or non-pancreatic lesions.

Results

Patients were 275 male and 190 females with a mean age of 59 years. Three-hundred twenty-seven patients had solid pancreatic lesions, while 138 had non-pancreatic lesions; 245 cases underwent EUS-FNA, and the remaining 211 cases underwent EUS-FNB. The presence of intact tissue core and sample adequacy was significantly higher in the FNB cases in solid pancreatic and non-pancreatic lesions. Blood contamination was significantly more in cell blocks and smears of EUS-FNA compared to that of EUS-FNB in solid pancreatic and non-pancreatic lesions. Based on histologic assessment of cell block only, EUS-FNB had more diagnostic accuracy (99%) than FNA (61%) (P-value < 0.005). However, cytological diagnosis by smears only showed no significant difference. The combined cytological and histological evaluation had 100% sensitivity, specificity, and accuracy.

Conclusion

EUS-FNA and EUS-FNB have comparable accuracy in diagnosing solid pancreatic and non-pancreatic lesions without ROSE. EUS-FNB is superior to EUS-FNA in acquiring intact tissue core and adequate samples with little blood contamination. Based on histological assessment (cell block/tissue core) only, EUS-FNA has less accuracy than EUS-FNB in diagnosing solid pancreatic lesions.
Constraints on fracture connectivity from amplitude variations with incidence angle and azimuth analysis
Authors: Tang Wei , Rubino J. Germán , Barbosa Nicolás D. , Solazzi Santiago G. , He Yanbin , Qi Yu , Li Jingye , Holliger Klaus
Published: June 2024

The analysis of seismic reflection amplitude variations with incidence angle and azimuth (AVAz) is a powerful tool for studying and characterizing fractured formations. There is evidence to suggest that wave-induced fluid pressure diffusion (FPD) within connected fractures can significantly affect the AVAz response. This, in turn, indicates that this seismic attribute may contain information on the connectivity degree of the fracture network, which represents a key hydraulic property of fractured formations. The assessment of the sensitivity of seismic reflectivity with respect to fracture connectivity accounting for FPD effects to date is limited to 2D models, which is mainly due to the complexity and the associated computational cost of modeling the effective properties of the corresponding generically anisotropic 3D media. To overcome these issues, we use a numerical upscaling procedure based on Biot’s theory of poroelasticity that allows us to obtain effective anisotropic representations of 3D fractured formations accounting for the FPD effects. Using these effective properties, we then perform a plane-wave analysis to compute the reflection coefficients at the top of the corresponding fractured formation. The results of our numerical analyses extend the previous 2D studies and demonstrate that seismic reflection coefficients are highly sensitive to the degree of connectivity of the fracture networks. The reflectivity responses of formations comprising connected and unconnected fractures indicate pronounced differences not only with respect to incidence angle but also with respect to azimuth. Quite importantly, our results also demonstrate that crossplots of commonly used AVAz coefficients permit us to identify regions with higher or lower fracture connectivity.
Safety and preliminary efficacy results of IBI389, an anti-CLDN18.2/CD3 bispecific antibody, in patients with solid tumors and gastric or gastro-esophageal tumors: A phase 1 dose escalation and expansion study.
Authors: Zheng Li , Ruihong Dai , Jieer Ying , Xu Qi , Guo Zengqing , Hu Changlu , Sun Yuping , Niu Zuoxing , Hao Jihui , Zhang Mingjun , Guanghai Dai , Hua Dong , Pan Yueyin , Wang Xin , Wei Shuqing , Chen Xiaobing , Yu Xinhe , Zhang Yulong , Zhou Hui , Bi Feng
Published: June 2024

2519

Background: CLDN18.2 expression has been observed in various solid tumors especially in gastric cancer, indicating its potential as a novel target for anti-tumor therapy. IBI389 is an anti-CLDN18.2/CD3 bispecific antibody that induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the membrane of tumor cells. Herein, we report preliminary results from a phase I study to evaluate safety and efficacy of IBI389 in patients (pts) with advanced solid tumors. Methods: Eligible pts with advanced solid tumors who failed or were intolerant to standard treatments were enrolled. The dose escalation of IBI389 monotherapy used intra-patient dose escalation with accelerated titration and the classic 3+3 design (0.003 µg/kg to 600 µg/kg). Selected dose levels were expanded in pts with advanced gastric/gastroesophageal junction cancer (G/GEJ C) and pancreatic ductal adenocarcinoma (PDAC). The primary objective was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 9, 2024, a total of 114 pts were enrolled (males: 67.5%, median age: 60.0 years, G/GEJ C: 32.5%, PDAC: 57.9%, stage IV: 81.6%). No dose-limiting toxicity (DLT) was observed during dose escalation. The MTD was not reached. In all pts, treatment-emergent adverse events (TEAEs) occurred in 112 (98.2%) pts including 76 (66.7%) pts with grade ≥3 TEAEs. Treatment-related adverse events (TRAEs) occurred in 111 (97.4%) pts including 63 (55.3%) pts with grade ≥3 TRAEs. The most common grade ≥3 TRAEs (≥ 4%) were gamma-glutamyl transferase increased (21.9%), lymphocyte count decreased (13.2%) and nausea (4.4%). Cytokine release syndrome (CRS) related adverse events occurred in 65 (57.0%) pts including 1 (0.9%) pts with grade 3 CRS and no grade 4 or 5 CRS. TEAEs leading to dose interruption and treatment discontinuation occurred in 44 (38.6%) and 8 (7.0%) pts. Preliminary efficacy of IBI389 was observed in pts with CLDN18.2 expression ≥10% (immunohistochemistry 2+/3+). In G/GEJ C pts with previous treatments ≥2 lines receiving IBI389 at various dose levels ranging from 10µg/kg to 600 µg/kg (n=26), 8 pts had partial response (PR) and 11 pts had stable disease (SD). The ORR was 30.8% (95%CI: 14.3-51.8) and DCR was 73.1% (95%CI: 52.2-88.4). Conclusions: IBI389 showed manageable safety profiles in pts with advanced solid tumors and preliminary efficacy in CLDN18.2-positive pts with G/GEJ C. Clinical trial information: NCT05164458 .
Safety and preliminary efficacy of EIK1001 in combination with pembrolizumab in participants with advanced solid tumors.
Authors: Tolcher Anthony W. , Rasco Drew W. , Johnson Melissa Lynne , Patel Manish R. , Alistar Angela Tatiana , Cohen Julia Wanda , Cho Carolyn , Wang Meihua , Kurland Etah
Published: June 2024

2521

Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response; however, not all patients benefit and some become refractory. EIK1001 is a Toll-like receptor (TLR)7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Study BDB001-101 was a Phase 1, open-label, dose-escalation/expansion study of EIK1001 as either monotherapy (mono Rx; previously reported) or combined with pembrolizumab (comb Rx). Enrollment criteria included participants (pts) ≥ age 18 with confirmed, RECIST-measurable advanced solid tumors. Primary study objectives included safety and tolerability, and secondary objectives included evaluation of dose-limiting toxicities, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy by RECIST 1.1. During comb Rx dose escalation, pts received a range of doses of EIK1001 (QW IV) in combination with pembrolizumab (200 mg Q3W). Results: Fifty-one pts (median age 67 [range 33 to 86]) with multiple, distinct histological tumor types and with a median of 3 prior Rx regimens were enrolled. Overall, a total of 42/51 (82.4%) comb Rx pts experienced a treatment-related adverse event (TRAE). A total of 9/51 (17.7%) experienced a ≥ Grade 3 TRAE, including fatigue, cytokine release syndrome (CRS), hemiparesis, hypertension, joint range of motion reduced, muscular weakness, pancreatitis, rash (maculopapular), skin plaque, and stomatitis. Overall, 5/51 (9.8%) experienced manageable CRS, with only 1 discontinuation due to CRS. There were no deaths due to TRAEs. Of the efficacy-evaluable pts (n = 50), complete response (CR) or partial response (PR) was observed for 7/50 (14.0%), including 3 CR and 4 PR. Disease control (including CR, PR, or stable disease) was observed in 24/50 (48.0%). The median duration of response was 10 months (range = 4 to 32 months). Responses were observed in pts with prior anti-PD-1 exposure as well as in those with low or negative PD-L1 tumor expression. EIK1001 PK was linear and dose-proportional, and combination with pembrolizumab did not affect EIK1001 PK. Conclusions: Overall, EIK1001 was well-tolerated with a manageable safety profile and showed encouraging preliminary efficacy across several tumor types in combination with pembrolizumab. Responses were observed even in heavily pretreated patients not anticipated to respond to pembrolizumab monotherapy. Further development of EIK1001 is underway. Clinical trial information: NCT03486301 .
The gut microbial characteristics and underlying mechanisms of patients with different clinical prognoses from immunotherapy by landmark analysis.
Authors: Liu Xinyu , Lu Bo , Jia Xinmiao , Tang Hao , Zhou Qingyang , Zeng Yanlin , Gao Xiaoxing , Chen Minjiang , Xu Yan , Wang Mengzhao , Qian Jiaming , Tan Bei
Published: June 2024

2606

Background: A subset of cancer patients could benefit long-termly from immune checkpoints inhibitors (ICIs), which was called smearing effect. Gut microbiota was widely found to be associated with the initial ICIs efficacy and immune-related adverse event (irAE). This study aimed to identify the baseline gut microbiota characteristics of long-benefit patients and explore the possible underlying mechanisms. Methods: Lung cancer patients initially treated with anti-PD-1/PD-L1 therapy were consecutively enrolled from May 2020 to September 2022. All patients were classified into Benefit group, Resistance group and Severe irAE group based on the long-term prognosis. The baseline gut microbiota characteristics were identified by metagenome sequencing. MelonnPan was used to predict the abundances of 79 metabolites. The sequences of autoantigen, lung cancer antigen and anticancer peptides (ACPs) from IEDB and CancerPPD databases were aligned against the scaftigs of fecal samples. Results: 54 patients were enrolled with 24 in Benefit group, 13 in Severe irAE group and 17 in Resistance group. The microorganism composition was significantly different between Benefit group and Resistance group ( P=0.03), while no difference between Benefit group and Severe irAE group ( P=0.93). The co-occurrence network showed the Benefit group patients had the most compact microbiota network. Metabolites prediction analyses showed the short chain fatty acids propionate ( P=0.005) and butyrate/isobutyrate ( P=0.03) were significantly enriched in Benefit group than Resistance group, wherein the acetyl-CoA pathway ( P=0.04) accounted for the largest proportion of butyrate-production ability difference. The beneficial species had more positive correlations with butyrate-producing enzymes ( P<0.001). The microbiota of irAE patients had abundant aligned sequences with antigen epitopes of multiple autoimmune diseases. The total counts of systemic lupus erythematosus-related epitopes were significantly more enriched in patients with immune-related colitis ( P=0.04), especially FDNGRRGRPVTGP ( P=0.02) and IDNGRRGRPITGP ( P=0.02). Likewise, the microbiota of patients with good ICIs efficacy tended to have more abundant cancer-related antigen counts ( P=0.07) and ACPs counts ( P=0.06). Strain-level analysis revealed Escherichia coli and Faecalibacterium prausnitziishowed a centralized trend of genomic variations based on different clinical phenotypes. Conclusions: Long-term benefit patients had converging characteristics of gut microbiota, which coevoluted a compact microbial community with high butyrate-producing ability. The microbiota molecular mimicry of autoimmune and tumor antigen might contribute to irAE and ICIs efficacy. The strain-level genomic variations of specific species may also play a role in clinical phenotypes.
Phase Ia/Ib trial on the safety and efficacy of mobocertinib in combination with T-DM1 for patients with HER2-mutant solid tumors (WJOG16022M).
Authors: Kanemura Hiroaki , TANIZAKI JUNKO , Matsumoto Koji , Masuishi Toshiki , Isobe Taichi , Kodama Hiroaki , Shimizu Toshio , Sunakawa Yu , Chiba Yasutaka , Yamamoto Nobuyuki , Nakagawa Kazuhiko , Hayashi Hidetoshi
Published: June 2024

3025

Background: Safety and efficacy of HER2 tyrosine kinase inhibitor (TKI) and anti-HER2 antibody-drug conjugate (ADC) in HER2-mutant solid tumors have not been investigated. Methods: Mobocertinib, a potent HER2 TKI plus T-DM1, an anti-HER2 ADC was evaluated in this phase I study. In a dose-finding cohort (phase Ia, pIa), the maximum tolerated dose was estimated in patients (pts) irrespective of HER2 mutational status. To further establish safety and evaluate preliminary efficacy, additional pts with HER2 mutations were enrolled in a dose-expansion cohort (phase Ib, pIb). Mobocertinib of 80, 120 to 160 mg was orally administered with intravenous T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint was to determine the recommended dose (RD) (pIa), and to evaluate the confirmed objective response rate (ORR) (pIb). Results: Between Nov 2022 and Jun 2023, a total of 28 pts, 6 in the pIa and 22 in the pIb were enrolled to this study (14 NSCLC; 4 cervical; 2 duodenal papilla; 2 pancreatic, median follow-up, 6.4 mo [range, 1.9 to 12.9 mo]). The median age was 54 (range, 40-84) years, 17 pts were female. Among 27 pts with HER2-mutant tumors, mutations in kinase domain were most common (66.7%). In the pIa cohort, 3 DLTs were observed with mobocertinib 120 mg, including grade 3 thrombocytopenia, grade 4 acute kidney injury, and drug withdrawal due to nausea and anorexia, while there was no DLT with 80 mg. The RD was therefore determined to be mobocertinib 80 mg plus T-DM1 3.6 mg/kg. Among 22 pts in the pIb, grade ≥ 3 AE occurred in 72.7% of pts; the common events (>5%) being thrombocytopenia (50.0%), diarrhea (13.6%), and anorexia (13.6%). No interstitial lung disease/pneumonitis was observed. The ORR was 28.6%, the disease control rate (DCR) was 71.4%, and median progression-free survival (mPFS) was 3.2 mo (95% CI 1.6, 6.1) in the pIb. In 27 pts with HER2 mutations across all cohorts, the ORR was 42.3%, the DCR was 76.9%, and mPFS was 4.3 mo (95% CI 2.7, 6.7). Additionally, in 13 pts with HER2-mutant NSCLC including those who had developed resistance to trastuzumab deruxtecan, the ORR was 53.8%, the DCR was 84.6%, and mPFS was 6.1 mo (95% CI 2.9, 6.3). Conclusions: The RD of this study treatment is mobocertinib 80 mg plus T-DM1 3.6 mg. Combination therapy of HER2 TKI and HER2 ADC demonstrated feasibility and potential efficacy for HER2-mutant solid tumors. Clinical trial information: 2051220070 .