bluuebunny/crossref_metadata_2025 huggingface dataset:
A deep learning framework for predicting disease-gene associations with functional modules and graph augmentation
Authors: Jia Xianghu , Luo Weiwen , Li Jiaqi , Xing Jieqi , Sun Hongjie , Wu Shunyao , Su Xiaoquan
Published: June 2024

Background

The exploration of gene-disease associations is crucial for understanding the mechanisms underlying disease onset and progression, with significant implications for prevention and treatment strategies. Advances in high-throughput biotechnology have generated a wealth of data linking diseases to specific genes. While graph representation learning has recently introduced groundbreaking approaches for predicting novel associations, existing studies always overlooked the cumulative impact of functional modules such as protein complexes and the incompletion of some important data such as protein interactions, which limits the detection performance.

Results

Addressing these limitations, here we introduce a deep learning framework called ModulePred for predicting disease-gene associations. ModulePred performs graph augmentation on the protein interaction network using L3 link prediction algorithms. It builds a heterogeneous module network by integrating disease-gene associations, protein complexes and augmented protein interactions, and develops a novel graph embedding for the heterogeneous module network. Subsequently, a graph neural network is constructed to learn node representations by collectively aggregating information from topological structure, and gene prioritization is carried out by the disease and gene embeddings obtained from the graph neural network. Experimental results underscore the superiority of ModulePred, showcasing the effectiveness of incorporating functional modules and graph augmentation in predicting disease-gene associations. This research introduces innovative ideas and directions, enhancing the understanding and prediction of gene-disease relationships.
Genome-wide identification and evolution of the tubulin gene family in Camelina sativa
Authors: Blume Rostyslav Y. , Rabokon Anastasiia M. , Pydiura Mykola , Yemets Alla I. , Pirko Yaroslav V. , Blume Yaroslav B.
Published: June 2024

Background

Tubulins play crucial roles in numerous fundamental processes of plant development. In flowering plants, tubulins are grouped into α-, β- and γ-subfamilies, while α- and β-tubulins possess a large isotype diversity and gene number variations among different species. This circumstance leads to insufficient recognition of orthologous isotypes and significantly complicates extrapolation of obtained experimental results, and brings difficulties for the identification of particular tubulin isotype function. The aim of this research is to identify and characterize tubulins of an emerging biofuel crop Camelina sativa.

Results

We report comprehensive identification and characterization of tubulin gene family in C. sativa, including analyses of exon-intron organization, duplicated genes comparison, proper isotype designation, phylogenetic analysis, and expression patterns in different tissues. 17 α-, 34 β- and 6 γ-tubulin genes were identified and assigned to a particular isotype. Recognition of orthologous tubulin isotypes was cross-referred, involving data of phylogeny, synteny analyses and genes allocation on reconstructed genomic blocks of Ancestral Crucifer Karyotype. An investigation of expression patterns of tubulin homeologs revealed the predominant role of N6 (A) and N7 (B) subgenomes in tubulin expression at various developmental stages, contrarily to general the dominance of transcripts of H7 (C) subgenome.

Conclusions

For the first time a complete set of tubulin gene family members was identified and characterized for allohexaploid C. sativa species. The study demonstrates the comprehensive approach of precise inferring gene orthology. The applied technique allowed not only identifying C. sativa tubulin orthologs in model Arabidopsis species and tracking tubulin gene evolution, but also uncovered that A. thaliana is missing orthologs for several particular isotypes of α- and β-tubulins.
Mycobiota contaminating some market cake samples with reference to their toxin and enzyme
Authors: Abdelhameed Shimaa M. , Khalifa Basma A.
Published: June 2024

Fungi can spoil the majority of baked products. Spoilage of cake during storage is commonly associated with fungi. Therefore, this study aimed to assess the quality of different types of cakes sold in the market. The most predominant fungal genera in the tested cake samples (14 samples) were Aspergillus spp., and Penicillium spp. On Potato Dextrose Agar (PDA), the medium fungal total count was 43.3 colonies /g. Aspergillus was the most dominant genus and was isolated from six samples of cake. Aspergillus was represented by 3 species namely, A. flavus, A. niger, and A. nidulans, represented by 13.32, 19.99, and 3.33 colonies /g respectively. On Malt Extract Agar (MEA) Medium, the fungal total count was 123.24 colonies / g. Aspergillus was the most dominant isolated genus from 11 samples of cake and was represented by 5 species, namely, A. flavus, A. niger, A. ochraceous, A. terreus, and A. versicolor (26. 65, 63.29, 3.33, 6.66, and 3.33 colonies / g , respectively). Twenty-four isolates (88.88 %) of the total tested twenty-seven filamentous fungi showed positive results for amylase production. Ten isolates (37.03%) of the total tested filamentous fungi showed positive results for lipase production, and finally eleven isolates (40.74 %) of the total fungal isolates showed positive results for protease production. Aflatoxins B1, B2, G1, G2, and ochratoxin A were not detected in fourteen collected samples of cake. In this study, clove oil was the best choice overpeppermint oil and olive oil for preventing mold development when natural agents were compared. It might be due to the presence of a varietyof bioactive chemical compounds in clove oil, whose major bioactive component is eugenol, which acts as an antifungal reagent. Therefore, freshly baked cake should be consumed within afew days to avoid individuals experiencing foodborne illnesses.
Prognostic value of red blood cell distribution width to albumin ratio for predicting mortality in adult patients meeting sepsis-3 criteria in intensive care units
Authors: Shan Xiaoxi , Li Zhishu , Jiang Jing , Li Wei , Zhan Jingyan , Dong Lixia
Published: June 2024

Background

Patients with sepsis with low albumin levels and high red blood cell distribution width levels have poor prognoses. Red blood cell distribution width to albumin ratio (RAR) has recently attracted attention as an innovative inflammation biomarker. We aimed to explore the association between RAR and the prognosis of patients with sepsis.

Methods

This retrospective observational study included 402 patients meeting the sepsis-3 standards admitted to Yantai Yuhuangding Hospital’s intensive care units (ICUs) between January 2020 and December 2022. The relationship between RAR and mortality in patients with sepsis was examined using regression analysis, Kaplan–Meier analyses, and a receiver operating characteristic curve. Subgroup and sensitivity analyses were conducted to assess the results’ robustness.

Results

RAR, when considered as a continuous variable, was a significant independent in-hospital mortality risk factor (adjusted odds ratio [OR]: 1.383; 95% confidence interval [CI]: 1.164–1.645; P < 0.001). When considering RAR as a categorical variable, the ORs (95% CIs) of hospital mortality for quartile 2 (Q2), Q3, and Q4 compared with Q1 were 1.027 (0.413–2.551), 3.632 (1.579–8.354), and 4.175 (1.625–10.729), respectively, P < 0.001. Similar outcomes were observed for 28- and 90-day mortalities.

Conclusions

RAR may indicate clinical prognosis for patients with sepsis in the ICU, potentially providing a low-cost, easily repeatable, and accessible biomarker for risk categorization for these patients.
CSPG4P12 polymorphism served as a susceptibility marker for esophageal cancer in Chinese population
Authors: Xu Hongxue , Yang Zhenbang , Hu Wenqian , Zhou Xianlei , Zhang Zhi , Zhang Xuemei
Published: June 2024

Background

Chondroitin sulfate proteoglycan 4 pseudogene 12 (CSPG4P12) has been implicated in the pathogenesis of various cancers. This study aimed to evaluate the association of the CSPG4P12 polymorphism with esophageal squamous cell carcinoma (ESCA) risk and to explore the biological impact of CSPG4P12 expression on ESCA cell behavior.

Methods

A case-control study was conducted involving 480 ESCA patients and 480 healthy controls to assess the association between the rs8040855 polymorphism and ESCA risk. The CSPG4P12 rs8040855 genotype was identified using the TaqMan-MGB probe method. Logistic regression model was used to evaluate the association of CSPG4P12 SNP with the risk of ESCA by calculating the odds ratios (OR) and 95% confidence intervals (95%CI ). The effects of CSPG4P12 overexpression on cell proliferation, migration, and invasion were examined in ESCA cell lines. Co-expressed genes were identified via the CBioportal database, with pathway enrichment analyzed using SangerBox. The binding score of CSPG4P12 to P53 was calculated using RNA protein interaction prediction (RPISeq). Additionally, Western Blot analysis was performed to investigate the impact of CSPG4P12 overexpression on the P53/PI3K/AKT signaling pathway.

Results

The presence of at least one rs8040855 G allele was associated with a reduced susceptibility to ESCA compared to the CC genotype (OR = 0.51, 95%CI = 0.28–0.93, P = 0.03). Stratification analysis revealed that the CSPG4P12 rs8040855 C allele significantly decreased the risk of ESCA among younger individuals (≤ 57 years) and non-drinkers (OR = 0.31, 95%CI = 0.12–0.77, P = 0.01; OR = 0.42, 95%CI=0.20–0.87, P = 0.02, respectively). CSPG4P12 expression was found to be downregulated in ESCA tissues compared to adjacent normal tissues. Overexpression of CSPG4P12 in ESCA cells inhibited their proliferation, migration, and invasion capabilities. Furthermore, Western Blot analysis indicated that CSPG4P12 overexpression led to a reduction in PI3K and p-AKT protein expression levels. P53 silencing rescues the inhibitory effect of CSPG4P12 on p-AKT.

Conclusion

The CSPG4P12 rs8040855 variant is associated with reduced ESCA risk and the overexpression of CSPG4P12 inhibited the migration and invasion of ESCA cells by P53/PI3K/AKT pathway. These findings suggest that CSPG4P12 may serve as a novel biomarker for ESCA susceptibility and a potential target for therapeutic intervention.
Basement membrane-associated gene expression as a predictor of survival in oral cancer
Authors: Wang Xu , Liu Chaoge , Wu HuiFang , Gu Yulu , Zhang Le , Xu Rongqing , Lin Qing
Published: June 2024

Background

This study sought to investigate the prognostic value of basement membrane (BM)-associated gene expressions in oral cancer.

Methods

We harvested and integrated data on BM-associated genes (BMGs), the oral cancer transcriptome, and clinical information from public repositories. After identifying differentially expressed BMGs, we used Cox and Lasso regression analyses to create a BMG-based risk score for overall survival at various intervals. We then validated this score using the GSE42743 cohort as a validation set. The prognostic potential of the risk scores and their relations to clinical features were assessed. Further, we conducted functional pathway enrichment, immune cell infiltration, and immune checkpoint analyses to elucidate the immunological implications and therapeutic potential of the BMG-based risk score and constituent genes. To confirm the expression levels of the BMG LAMA3 in clinical samples of oral cancer tissue, we performed quantitative real-time PCR (qRT-PCR) and immunohistochemical staining.

Results

The BMGs LAMA3, MMP14, and GPC2 demonstrated notable prognostic significance, facilitating the construction of a BMG-based risk score. A higher risk score derived from BMGs correlated with a poorer survival prognosis for oral cancer patients. Moreover, the risk-associated BMGs exhibited a significant relationship with immune function variability (P < 0.05), discrepancies in infiltrating immune cell fractions, and immune checkpoint expressions (P < 0.05). The upregulated expression levels of LAMA3 in oral cancer tissues were substantiated through qRT-PCR and immunohistochemical staining.

Conclusion

The BMG-based risk score emerged as a reliable prognostic tool for oral cancer, meriting further research for validation and potential clinical application.
Effect of duloxetine on changes in serum proinflammatory cytokine levels in patients with major depressive disorder
Authors: Gao Wenfan , Gao Yejun , Xu Yayun , Liang Jun , Sun Yanhong , Zhang Yuanyuan , Shan Feng , Ge Jinfang , Xia Qingrong
Published: June 2024

Objective

Accumulating evidence supports the idea that inflammation may contribute to the pathophysiology of major depressive disorder (MDD). Duloxetine, a serotonin-norepinephrine reuptake inhibitor, exhibits anti-inflammatory effects both in vitro and in vivo. In this study, we investigated the impact of duloxetine on changes in serum proinflammatory cytokine levels among individuals diagnosed with MDD.

Methods

A cohort of 23 drug-naïve individuals diagnosed with MDD and 23 healthy controls were included in this study. The severity of depressive symptoms was evaluated using the 24-item Hamilton Depression Scale (HAMD-24). A panel of 7 proinflammatory cytokines, including interleukin-1β (IL-1β), IL-2, IL-6, IL-8, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), were quantified using multiplex Luminex assays. The levels of serum cytokines in healthy controls and patients with MDD were compared at baseline. All patients received duloxetine at a dosage range of 40–60 mg/day for a duration of 4 weeks. The HAMD-24 scores and serum cytokine levels were compared before and after duloxetine treatment.

Results

Compared with healthy controls, patients with MDD had significantly greater levels of IL-2, IL-6, IL-8, IL-12, TNF-α, and IFN-γ (P < 0.05). Moreover, there was a significant decrease in HAMD-24 scores observed pre- and post-treatment (t = 13.161, P < 0.001). Furthermore, after 4 weeks of treatment, the serum levels of IL-8 (t = 3.605, P = 0.002), IL-12 (t = 2.559, P = 0.018), and IFN-γ (t = 3.567, P = 0.002) decreased significantly. However, there were no significant differences in other cytokines, including IL-1β, IL-2, IL-6, and TNF-α, before and after treatment (P > 0.05).

Conclusions

These findings present compelling evidence, potentially for the first time, indicating that duloxetine treatment may effectively reduce the serum concentrations of IL-8, IL-12, and IFN-γ in individuals diagnosed with MDD. However, the precise mechanisms underlying this effect remain unclear and warrant further investigation.
Co-occurrence of obesogenic behaviors and their implications for mental health during the COVID-19 pandemic: a study with university students
Authors: Barbosa Bruna Carolina Rafael , de Deus Mendonça Raquel , Machado Elaine Leandro , Meireles Adriana Lúcia
Published: June 2024

Background

The university years are a critical period for young adults, as they are more exposed to obesogenic behaviors and experience stressful situations that compromise their mental health. This study aims to estimate the prevalence of anxiety and depression symptoms and evaluate the association between the combined occurrence of obesogenic behaviors among university students.

Methods

A cross-sectional study was conducted on students from a public university in Brazil during the COVID-19 pandemic. Data were collected from July to August 2020 using an online questionnaire. The outcome variables (anxiety and depression symptoms) were assessed using the Depression, Anxiety and Stress Scale-21 (DASS-21). The co-occurrence of obesogenic behaviors was measured based on irregular consumption of fruits and vegetables, frequent consumption of ultra-processed foods, physical inactivity during leisure time, and sedentary behavior. A Venn diagram was used for the exploratory analysis. To verify the association between the outcome and explanatory variables, a directed acyclic graph model was constructed, and multivariate logistic regression was performed to calculate odds ratios (ORs) and 95% confidence intervals (95%CIs).

Results

A total of 1,353 students aged 18–24 years participated in this study. Symptoms of anxiety and depression were present in 46.1% and 54.6% of the participants, respectively. The most prevalent combination of obesogenic behaviors was frequent consumption of ultra-processed foods, physical inactivity during leisure time, and sedentary behavior (17.2%). The greater the number of simultaneous obesogenic behaviors, the higher the chance to present symptoms of anxiety [OR: 2.81 (95%CI: 1.77–4.46)] and depression [OR: 3.46 (95%CI: 2.20–5.43)].

Conclusion

These findings reinforce the need to take actions to promote mental health in the university environment in conjunction with programs to promote a healthy lifestyle and improve the physical and mental well-being of students.
Benefits of uric acid-lowering medication after bariatric surgery in patients with gout
Authors: Song Ke , He Ming , Kong Xiangxin , Xian Yin , Zhang Yuan , Xie Xing , Xie Sijun , Jia Aimei , Ren Yixing
Published: June 2024

Background/Purpose

Patients with gout are at risk for increased serum uric acid (SUA) levels and gout attacks in the short term after undergoing bariatric surgery, and the purpose of this study was to evaluate the benefits of short-term treatment with uric acid-lowering medication after bariatric surgery for the control of gout attacks and SUA levels in patients with gout.

Methods

71 patients who underwent SG from January 2020 to December 2022 were prospectively included. These patients were diagnosed with hyperuricemia before surgery and had a history of gout attacks. Patients were classified into a drug-treatment group (DTG, n = 32) and a non-drug-treatment group (NDTG, n = 39) according to whether they took uric acid-lowering medication after surgery. Changes in the number of gout attacks, body mass index (BMI), and SUA levels at 1 week, 1 month, 3 months, and 6 months after bariatric surgery were measured in both groups.

Results

In the DTG, 22 patients (68.8%) experienced an increase in SUA within 1 week, 3 patients (9.4%) had an acute attack of gout within the first month, and no patients had a gout attack thereafter. In the NDTG, 35 patients (89.7%) experienced an increase in SUA within 1 week, 7 patients (17.9%) had an acute gout attack within the first month, and 4 patients (10.3%) experienced gout attacks between month 1 and month 3 postoperatively. Both groups were free of gout attacks between the 3rd and 6th postoperative month and showed a significant decrease in SUA and BMI by the sixth month.

Conclusion

In patients with gout, continued use of uric acid-lowering medication after bariatric surgery is beneficial in reducing the number of gout attacks and the risk of rising SUA.
The effect of platelet-rich fibrin (PRF) versus freeze-dried bone allograft (FDBA) used in alveolar ridge preservation on the peri-implant soft and hard tissues: a randomized clinical trial
Authors: Azangookhiavi Hassan , Habibzadeh Sareh , Zahmatkesh Houyar , Mellati Ehsan , Mosaddad Seyed Ali , Dadpour Yalda
Published: June 2024

Background

The effectiveness of alveolar ridge preservation on bone regeneration and tissue healing has been thoroughly documented in the literature. This study aimed to evaluate the peri-implant soft and hard tissue changes after alveolar ridge preservation using either platelet-rich fibrin (PRF) or freeze-dried bone allograft (FDBA) over a 12-month period following the prosthetic loading of implants.

Methods

In this randomized clinical trial, 40 individuals were recruited for alveolar ridge preservation using (1) FDBA or (2) PRF in incisal/premolar areas. At two follow-up sessions (six- and 12-months post-implant insertion), radiographic imaging and clinical examinations assessed marginal bone loss and soft tissue factors, including gingival recession and bleeding on probing. The differences between study groups were analyzed using Generalized estimating Equations, the Binary logistic regression model, and Cochran’s Q test.

Results

There was a statistically significant difference regarding gingival recession at both follow-up evaluations; values in the PRF group were considerably lower compared to the FDBA group (p < 0.05). The mean values for vertical marginal bone loss and bleeding on probing showed no significant differences between the two study groups (p > 0.05).

Conclusions

Except for gingival recession, applying PRF yielded comparable clinical results to FDBA after one year of implant loading and could be recommended as a potential biomaterial for alveolar ridge preservation following tooth extractions.

Clinical trial registration

The research protocol was registered in the Protocol Registration and Results System on 13/08/2021, available athttps://clinicaltrials.gov/(NCT05005377).
Associations of clinical context-specific ambiguity tolerance with burnout and work engagement among Japanese physicians: a nationwide cross-sectional study
Authors: Fujikawa Hirohisa , Aoki Takuya , Ando Takayuki , Haruta Junji
Published: June 2024

Purpose

Ambiguity tolerance specific to the clinical context – in contrast to ambiguity tolerance as a personality trait – may vary with experience and has received considerable attention. Although this tolerance appears to be related to burnout and work engagement, few studies have examined this association among physicians. Thus, we aimed to examine the relationships between clinical context-specific ambiguity tolerance, burnout, and work engagement among physicians in Japan.

Methods

We conducted a nationwide cross-sectional study in Japan. We invited family physicians from 14 family medicine residency programs and physicians with specialties other than family medicine from monitors of an Internet survey company to participate in the study. We measured ambiguity tolerance in the clinical context using the Japanese version of the Tolerance of Ambiguity in Medical Students and Doctors (J-TAMSAD) scale, burnout using the Japanese version of the Burnout Assessment Scale (BAT-J), and work engagement using the Utrecht Work Engagement Scale (UWES). We performed a multivariable linear regression analysis to determine whether the J-TAMSAD scale score was associated with the BAT-J and UWES scores.

Results

383 respondents were included in the analysis. After adjustment for possible confounders, clinical context-specific ambiguity tolerance showed a dose-dependent negative association with burnout (adjusted mean difference  -0.39, 95% confidence interval (CI) -0.56 to -0.22 for the highest J-TAMSAD score quartile compared with the lowest). Ambiguity tolerance in the clinical context also showed a dose-dependent positive association with work engagement (adjusted mean difference 0.83, 95% CI 0.49 to 1.16 for the highest J-TAMSAD score quartile compared with the lowest).

Conclusions

Our study showed that tolerance for ambiguity in the clinical context was negatively associated with burnout, and positively associated with work engagement. These findings will be useful in developing interventions aimed at preventing burnout and promoting work engagement among physicians.
ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages
Authors: Hua Xin , Xu Qiuli , Wu Ranpu , Sun Wei , Gu Yanli , Zhu Suhua , Liu Xin , Lv Tangfeng , Song Yong
Published: June 2024

Background

Understanding the mechanisms that mediate the interaction between tumor and immune cells may provide therapeutic benefit to patients with cancer. The N6-methyladenosine (m6A) demethylase, ALKBH5 (alkB homolog 5), is overexpressed in non-small cell lung cancer. However, its role in the tumor microenvironment is unknown.

Methods

Datasets and tissue samples were used to determine the relationship between ALKBH5 expression and immunotherapy efficacy. Bioinformatic analysis, colorimetric assay to determine m6A RNA methylation, dual luciferase reporter assay, RNA/m6A-modified RNA immunoprecipitation, RNA stability assay, and RNA sequencing were used to investigate the regulatory mechanism of ALKBH5 in non-small cell lung cancer. In vitro and in vivo assays were performed to determine the contribution of ALKBH5 to the development of non-small cell lung cancer.

Results

ALKBH5 was upregulated in primary non-small cell lung cancer tissues. ALKBH5 was positively correlated with programmed death-ligand 1 expression and macrophage infiltration and was associated with immunotherapy response. JAK2 was identified as a target of ALKBH5-mediated m6A modification, which activates the JAK2/p-STAT3 pathway to promote non-small cell lung cancer progression. ALKBH5 was found to recruit programmed death-ligand 1-positive tumor-associated macrophages and promote M2 macrophage polarization by inducing the secretion of CCL2 and CXCL10. ALKBH5 and tumor-associated macrophage-secreted IL-6 showed a synergistic effect to activate the JAK2/p-STAT3 pathway in cancer cells.

Conclusions

ALKBH5 promotes non-small cell lung cancer progression by regulating cancer and tumor-associated macrophage behavior through the JAK2/p-STAT3 pathway and the expression of CCL2 and CXCL10, respectively. These findings suggest that targeting ALKBH5 is a promising strategy of enhancing the anti-tumor immune response in patients with NSCLC and that identifying ALKBH5 status could facilitate prediction of clinical response to anti-PD-L1 immunotherapy.
Effectiveness of remote risk-based monitoring and potential benefits for combination with direct data capture
Authors: Yamada Osamu , Chiu Shih-Wei , Nakazawa Toru , Tsuda Satoru , Yoshida Mitsuhide , Asano Toshifumi , Kokubun Taiki , Hashimoto Kazuki , Takata Munenori , Ikeda Suzuka , Kawabe Yosuke , Tamura Yuko , Yamaguchi Takuhiro
Published: June 2024

Background

In recent years, alternative monitoring approaches, such as risk-based and remote monitoring techniques, have been recommended instead of traditional on-site monitoring to achieve more efficient monitoring. Remote risk-based monitoring (R2BM) is a monitoring technique that combines risk-based and remote monitoring and focuses on the detection of critical data and process errors. Direct data capture (DDC), which directly collects electronic source data, can facilitate R2BM by minimizing the extent of source documents that must be reviewed and reducing the additional workload on R2BM. In this study, we evaluated the effectiveness of R2BM and the synergistic effect of combining R2BM with DDC.

Methods

R2BM was prospectively conducted with eight participants in a randomized clinical trial using a remote monitoring system that uploaded photographs of source documents to a cloud location. Critical data and processes were verified by R2BM, and later, all were confirmed by on-site monitoring to evaluate the ability of R2BM to detect critical data and process errors and the workload of uploading photographs for clinical trial staff. In addition, the reduction of the number of uploaded photographs was evaluated by assuming that the DDC was introduced for data collection.

Results

Of the 4645 data points, 20.9% (n = 973, 95% confidence interval = 19.8–22.2) were identified as critical. All critical data errors corresponding to 5.4% (n = 53/973, 95% confidence interval = 4.1–7.1) of the critical data and critical process errors were detectable by R2BM. The mean number of uploaded photographs and the mean time to upload them per visit per participant were 34.4 ± 11.9 and 26.5 ± 11.8 min (mean ± standard deviation), respectively. When assuming that DDC was introduced for data collection, 45.0% (95% confidence interval = 42.2–47.9) of uploaded photographs for R2BM were reduced.

Conclusions

R2BM can detect 100% of the critical data and process errors without on-site monitoring. Combining R2BM with DDC reduces the workload of R2BM and further improves its efficiency.
Simulation of gravity field estimation of Phobos for Martian Moon eXploration (MMX)
Authors: Yamamoto Keiko , Matsumoto Koji , Ikeda Hitoshi , Senshu Hiroki , Willner Konrad , Ziese Ramona , Oberst Jürgen
Published: June 2024

We study the dynamic orbit about Phobos of the Martian Moon eXploration (MMX) spacecraft and simulate gravity field estimation using Doppler, image landmarks, and LIght Detection And Ranging (LIDAR) data based on a mission plan of MMX and investigate whether the differences in the internal density structure of Phobos can be detected through this mission. Degree 2 Stokes coefficients of the Phobos gravity field, $${\overline{C} }_{20}$$

C
¯

20

and $${\overline{C} }_{22}$$

C
¯

22

, which are necessary to obtain the moment of inertia by combining with the libration amplitude, could be determined with an accuracy within the order of 0.1% using datasets from two-dimensional (2D) quasi-satellite orbits (QSOs). If observations from 3D-QSO could be realized at low altitude, coefficients up to degree and order 5 could be estimated, which could be used to detect regional density anomalies. Moreover, the observation data from the ascending trajectory after landing on the Phobos surface can be used to detect local density anomalies around the landing site, which could help interpret the origin of the samples and understand the internal structure of Phobos.

Graphical Abstract
Exploring the utilization and perceptions of pre-travel health consultations in primary care settings in Saudi Arabia: a cross-sectional study
Authors: AlAmer Naheel A. , AlQarni Amani M.
Published: June 2024

Background

International travel exposes individuals to diverse health risks, necessitating proactive pre-travel health preparations. Saudi Arabia has witnessed increased outbound travel. This study addresses a critical gap in knowledge by investigating the utilization and perceptions of pre-travel health consultations among adults in the Eastern Province of Saudi Arabia.

Methods

This cross-sectional study surveyed patients at the Family and Community Medicine Center of Imam Abdulrahman Bin Faisal University during January 2024 to explore perceptions of pre-travel health consultations among the Saudi Arabian population. Adults aged 18 years or older in the waiting area were invited to complete a self-administered questionnaire.

Results

Of the 772 participants, 624 (80.8%) engaged in international travel within the last year. However, 593 (76.8%) had never sought pre-travel health consultations. Age, gender, and education level significantly influenced the pursuit of pre-travel health advice, with older individuals, females, and those with higher educational attainment more likely to seek consultations. Participants perceived vaccination recommendations (597, 77.4%) and disease prevention information (678, 87.8%) as crucial parts of pre-travel health consultations. However, barriers to seeking advice included perceived low risk (445, 74.8%), lack of awareness (215, 36.3%), time constraints (128, 21.6%), and cost concerns (92, 15.5%).

Conclusion

The low prevalence of pre-travel health consultations among travelers highlights the need for targeted educational campaigns and the integration of travel health services into primary healthcare. Addressing the identified barriers and leveraging preferred information sources are crucial steps towards enhancing the uptake of pre-travel health consultations, ultimately improving the health and safety of international travelers from the region.
Emerging Novel Functional Imaging and Immunotherapy in Renal Cell Carcinoma and Current Treatment Sequencing Strategies After Immunotherapy
Authors: Ali Muhammad , Eid Marc , Saliby Renee Maria , Choi Sharon , McKay Rana R. , Siva Shankar , Braun David A. , Chen Yu-Wei
Published: June 2024

The management of renal cell carcinoma (RCC) has advanced significantly in the past two decades. Many promising functional imaging modalities such as radiolabeled tracer targeting carbonic anhydrase IX and prostate-specific membrane antigen are under development to detect primary kidney tumors, stage systemic disease, and assess treatment response in RCC. Immune checkpoint inhibitors targeting PD-1 and cytotoxic T-cell lymphocyte-4 have changed the treatment paradigm in advanced RCC. Trials investigating novel mechanisms such as LAG-3 immune checkpoint inhibition, chimeric antigen receptor T-cell therapies, and T-cell engagers targeting RCC-associated antigens are currently ongoing. With the rapidly changing treatment landscape of RCC, the treatment sequence strategies will continue to evolve. Familiarity with the toxicities associated with the therapeutic agents and how to manage them are essential to achieve optimal patient outcomes. This review summarizes the recent developments of functional imaging and immunotherapy strategies in RCC, and the evidence supports treatment sequencing.
Safety and efficacy of CyberKnife radiosurgery plus anlotinib hydrochloride in patients with recurrent glioblastoma: A prospective phase II single-arm study.
Authors: Guan Yun , Zhu Huaguang , Li Jing , Zou Wei , Pan Li , Wang Yang , Liu Ying , Wang Enmin , Wang Xin
Published: June 2024

2050

Background: Glioblastoma (GBM) is a tumor known for its highly vascular nature and limited treatment options upon disease recurrence. While Bevacizumab which target VEGF-A has gained approval for treating recurrent glioblastoma, the multi-target tyrosine kinase inhibitor Anlotinib has the ability to directly target Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet-Derived Growth Factor Receptor (PDGFR), and Fibroblast Growth Factor Receptor (FGFR). Theoretically, its anti-angiogenic effect may exceed that of Bevacizumab, and preliminary studies have shown its therapeutic efficacy in recurrent GBM (rGBM), indicating promising treatment potential. This study aims to present findings regarding the effectiveness and safety of combining Anlotinib with stereotactic radiosurgery (SRS) in treating patients with rGBM. Methods: Patients who underwent surgery, standard radiotherapy, and temozolomide chemotherapy and were diagnosed with recurrence based on Response Assessment in Neuro-Oncology (RANO) criteria and/or biopsy were eligible for inclusion. Each patient underwent CyberKnife SRS (25Gy/5fx) in combination with oral administration of Anlotinib (12 mg, daily, days 1–14/3 weeks) until encountering disease progression or experiencing intolerable adverse effects. The primary objective was the investigator-assessed median overall survival (OS) using the Response Assessment in Neuro-Oncology (RANO) criteria. Results: Between December 2019 and July 2023, 22 patients (median age: 55 years; range: 28–70) were included. According to RANO criteria, 21 patients exhibited tumor response, with 6 achieving complete response, resulting in an objective response rate of 95.5%. Additionally, one patient maintained stable disease without progression. Median progression-free survival (PFS) was 9.1 months (95% CI, 7.5–24.7), with a 6-month PFS rate of 85.7% (95% CI, 71.9–100.0). Median overall survival was 19.5 months (95% CI, 10.6–46.8). Common adverse events included hand-foot skin reactions (40.9%), hypercholesterolemia (27.3%), and hypertension (22.7%). Four patients experienced grade 3 adverse events, accounting for an 18.2% incidence rate. Therapy discontinuation due to ischemic stroke (grade 3) occurred in one patient. No grade 4 events or treatment-related deaths were reported. Conclusions: The combination of salvage SRS with Anlotinib demonstrated promising outcomes and manageable toxicity in managing recurrent GBM. Currently, a phase II randomized controlled trial, supported by the Shanghai Municipal Commission of Health, is underway. This trial aims to compare the efficacy of Anlotinib combined with radiosurgery against Bevacizumab combined with radiosurgery for the treatment of rGBM patients, further exploring this therapeutic regimen. Clinical trial information: NCT04197492 .
A phase 1 study of the small-molecule PD-L1 inhibitor INCB099280 in select advanced solid tumors: Updated safety, efficacy, and pharmacokinetics (PK) results.
Authors: Prenen Hans , Daniel Jeannie , Ebiana Victoria , Howe Jason , Gong Xiaohua , Spitz Susan , Italiano Antoine
Published: June 2024

2608

Background: INCB099280 has shown preliminary efficacy and acceptable safety in an ongoing phase 1, open-label, multicenter study in patients (pts) with advanced solid tumors (1). Here we present updated results and PK data. Methods: Eligible pts were ≥18 years of age with ECOG PS ≤1 and disease progression after available treatment (tx) or were ineligible for/without access to standard tx. Study started with dose escalation (100 mg qd to 800 mg bid), followed by dose expansion in 3 cohorts (IO-naive; IO-naive, MSI-H/dMMR tumors; anti–PD-1 previously treated). Primary endpoints are safety, tolerability, and determination of pharmacologically active dose/MTD. PK, objective response rate (ORR) per RECIST v1.1, and pharmacologic biomarkers were also analyzed. Results: As of January 14, 2023, 179 pts had received INCB099280 at doses from 100 mg qd to 800 mg bid (median age, 63 years [range, 21-86]; ≥2 prior lines of tx, 65.4%; prior IO, 16.2%). MTD was not reached. Overall, 96.6% of pts had ≥1 tx-emergent adverse events (TEAEs). Immune-related (ir) TEAEs occurred in 23.5% of pts. Best antitumor activity was noted with 400 mg bid (ORR, 17.8%) in pts with mixed tumor types. Updated clinical data will be presented. PK exposures increased proportionally as dose increased up to 800 mg bid (Table). Steady-state PK was achieved by cycle 1 day 8, with an accumulation ratio of 2-3. Inter-individual PK variability was high, but similar to that of healthy participants. Steady-state trough concentrations exceeded IC90 across 300-800 mg bid doses. In preliminary analyses correlating exposure with clinical outcomes, increased exposure was associated with a moderate trend of higher ORR and incidence of serious and/or ir-TEAEs. Preliminary electrocardiogram data suggested that large QTc effects (>20 ms) can be excluded at doses up to 800 mg bid. No association was detected between PK exposure and ctDNA change at cycle 4 day 1 or end-of-tx vs baseline, but decreased ctCNA was seen in all complete responders (n=2) and 6 partial responders (n=11). Conclusions: INCB099280 was generally well tolerated at all doses tested and showed promising antitumor activity. INCB099280 PK was dose proportional up to 800 mg bid, with high variability; steady-state trough exposure exceeded IC90 for ≥300 bid doses. These data support further development of INCB099280 as monotherapy and in combination regimens for solid tumors. Phase 2 studies are ongoing. 1. Prenen, ESMO-IO 2023; NCT04242199. Clinical trial information: NCT04242199 . [Table: see text]
A phase 2a study of NT-I7 (efineptakin alfa), a long-acting IL-7, and pembrolizumab to evaluate efficacy, including overall survival, in hard-to-treat gastrointestinal tumors.
Authors: Kim Richard D. , Mamdani Hirva , Barve Minal A. , Johnson Melissa Lynne , Murphy Julie A. , Trogun Lauren , Ferrando-Martinez Sara , Lee Byung Ha , Yang Se Hwan , Chaney Marya F. , Naing Aung
Published: June 2024

2621

Background: Microsatellite-stable colorectal (MSS-CRC) and pancreatic cancer (PDAC) are immunologically cold tumors with null response to checkpoint inhibitors (CPI). NT-I7, a long-acting IL-7, in combination with pembrolizumab (pembro) has shown to significantly increase intratumoral T cell infiltration and elicit some tumor control in these hard-to-treat gastrointestinal indications. The original MSS-CRC and PDAC cohorts, enrolling 25 patients (pts) each, were expanded to 50 pts per indication. Here, we provide an updated analysis including the original and expansion cohorts. Methods: Open-label Phase 2a study in subjects with relapsed/refractory CPI-naïve MSS-CRC and PDAC; NT-I7 1200 µg/kg IM every 6 weeks (Q6W), pembro 200 mg IV Q3W. Antitumor activity assessed by RECIST v1.1/iRECIST. Results: As of 02OCT2023, 98 subjects were efficacy-evaluable (50 MSS-CRC, 48 PDAC); median age 61.0 years, all with baseline ECOG status 0-1. 95.9% (94/98) received study treatment ≥3rd line, with a median follow -up of 6.1 months. Safety profile for NT-I7 was similar to previous reports. In MSS-CRC pts, 1 pt and 3 pts achieved confirmed partial responses per RECIST and iRECIST, respectively; median duration of response (DOR/iDOR) was 13.1/13.0 months (mo) and 2 responders were alive with no progression at data cutoff. Disease control rate (DCR/iDCR) was 36.0% (18/50) / 38.0% (19/50), with a duration of response and stable disease (DORSD/iDORSD) of 3.2/14.5mo. Interestingly, iDCR was 71.4% (5/7) in MSS-CRC pts with primary tumor in the rectum, versus 30.8% (12/39) in pts with primary tumor in the colon. With 11 pts on follow up, progression free survival (PFS/iPFS) was 1.5/3.8 mo. Among PDAC pts, 2 and 3 pts achieved confirmed PR and iPR, with DOR/iDOR of NE/9.7 mo; 1 responder was alive with no progression at data cutoff. DCR/iDCR was 25.0% (12/48) / 27.1% (13/48), and DORSD/iDORSD was 2.9/9.8mo. With 11 pts on follow up, PFS/iPFS was 1.4/2.1 mo. Clinical benefit in MSS-CRC and PDAC was most evident by a notable median overall survival (mOS); 13.2 mo in MSS-CRC [95% CI 8.9 – 18.6 mo] and 11.1 mo in PDAC [95% CI 4.1 – 13.3 mo], compared to historical mOS for standard of care, 10.8 mo (MSS-CRC) and 6.1 mo (PDAC). Conclusions: NT-I7 and pembro treatment was associated with longer mOS relative to historical studies. Identification of predictive biomarkers that may define pts with higher likelihood of clinical benefit would be a promising step to maximizing potential of the NT-I7 + pembro treatment combination for pts with these indications. Research in this area is ongoing. Clinical trial information: NCT04332653 .
AMPLIFY-7P, a first-in-human safety and efficacy trial of adjuvant mKRAS-specific lymph node targeted amphiphile ELI-002 7P vaccine in patients with minimal residual disease–positive pancreatic and colorectal cancer.
Authors: Devoe Craig E. , Pant Shubham , Wainberg Zev A. , Chung Vincent , George Thomas J. , Kasi Pashtoon Murtaza , VanWyk Haley , Tavares Amy , Perry James , Kheoh Thian , McNeil Lisa , Welkowsky Esther , DeMuth Peter , Haqq Christopher M. , O'Reilly Eileen M.
Published: June 2024

2636

Background: Diverse KRAS mutations occur in 25% of solid tumors with G12D, V and R most frequent. ELI-002 7P is an expanded spectrum vaccine comprised of lymph-node targeted Amphiphile (Amph)-modified G12D, V, R, C, S, A, and G13D mutant KRAS peptides with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Earlier ELI-002 2P showed high rates of T cell and tumor biomarker response (both 21/25, 84%), with median relapse-free survival not reached versus 4.01 months (HR 0.14; p=0.0167) comparing patients (pts) above versus below T cell median (12.75X). Methods: This multicenter phase IA trial assessed safety, immunogenicity and preliminary antitumor activity of ELI-002 7P in pancreatic (PDAC) and colorectal pts with minimal residual disease (MRD) following standard locoregional treatment. Pts with elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker (CA19-9/CEA), and KRAS mutation were enrolled and treated with subcutaneous fixed dose Amph-CpG-7909 and 1.4 mg or 4.9 mg of Amph-Peptides 7P (Table). Safety, T cell change, and preliminary antitumor activity including biomarker reduction/clearance are reported. Results: No dose-limiting toxicities, no treatment related SAEs or cytokine release syndrome were observed, no maximum tolerated dose was identified, and the recommended phase 2 dose (RP2D) was 10.0 mg Amph-CpG-7909 with 4.9 mg Amph-Peptides 7P. Safety: all grade 1, fatigue (29%), malaise (21%), and injection site reaction (7.1%). At data cutoff Dec 18, 2023, polyfunctional mKRAS-specific T cells were observed in 100% (n=11/11). Both CD8+ and CD4+ responses were induced in 63.6% of pts (7/11), with higher median fold-change from baseline at RP2D and durable responses post-booster immunization in 100% of pts (7/7). Biomarker reductions were observed in 2/5 (40%) at the 1.4 mg Amph-Peptides 7P dose level and in 5/7 (71%) at the RP2D 4.9 mg dose level in pts with all the common G12X (D, V, R) and G13 (D) KRAS mutations; MRD clearance was observed in 1 G12V PDAC pt at 4.9mg. Conclusions: ELI-002 7P was safe with median RP2D T cell responses exceeding the prior formulation (7P median 109.2; 2P 12.75), and early indications of antitumor activity. The randomized phase II is now open in patients with pancreas cancer. Clinical trial information: NCT05726864 . [Table: see text]
Updated safety, efficacy, pharmacokinetics, and biomarkers from the phase 1 study of IMC-002, a novel anti-CD47 monoclonal antibody, in patients with advanced solid tumors.
Authors: Lim Ho Yeong , Ahn Jin Seok , Park Joon Oh , Hong Jung Yong , Lee Sung Young , Jeong Haeun , Yun Hwi-yeol , Shin Seunghwan , Ock Chan-Young , Kim Heung Tae Tae
Published: June 2024

2642

Background: Preliminary safety and efficacy data from the phase 1a dose escalation study of IMC-002 has been reported, showing no dose limiting toxicity (DLT) across 4 dose levels. Here we present updated insight into safety, efficacy, optimal dose determination through pharmacokinetics (PK) modeling, and CD47 expression. Methods: Eligible pts had metastatic or locally advanced solid tumors that progressed following at least 1 prior systemic therapy and an ECOG PS ≤1. A traditional 3+3 design was employed to evaluate DLT over 21 days, administering 4 doses of IMC-002 (5, 10, 20 and 30 mg/kg) every 2 weeks (Q2W). Tumor assessments were performed Q6W using RECIST 1.1. Optimal dosing was determined through target-mediated drug disposition (TMDD) PK modeling, incorporating FcRn recycling. CD47 immunohistochemistry (IHC) images were analyzed with an AI analyzer (Lunit SCOPE) that can distinguish staining positivity and cell type at the single cell level. Results: A total of 12 refractory patients (hepatocellular carcinoma 9, breast cancer 2, gallbladder cancer 1) were received IMC-002 with a median follow-up of 11 months (max 19 months). All treatment related adverse events (TRAEs) were grade 1-2 (92%) and TRAEs observed with over 20% incidence included skin rash, transient floaters and anemia. After the initial exposure, there was a decrease in hemoglobin levels, but these levels subsequently recovered without the evidence of hemolytic anemia. Among the 12 efficacy evaluable patients, the disease control rate was 50.0% and the clinical benefit rate (CBR, stable disease ≥ 6 months of treatment) was 33.3% with a median treatment duration of 10 months. Based on PK modeling, 20 mg/kg Q3W was selected as optimal RP2D. In the AI analysis of CD47 IHC, the density of CD47 positive macrophages tended to be higher in case with CBR compared to non-CBR cases (mean CD47+ macrophage density: 71.0 vs 44.3/mm2), while the percentage of tumor cells expressing CD47 was similar between the two groups (mean CD47+ tumor cells: 54.5 vs 59.8%). Conclusions: IMC-002 has an excellent safety profile when administered intravenously at a dose of up to 30 mg/kg every 2 weeks intravenously for max 12 months treatment. IMC-002 monotherapy demonstrates meaningful clinical benefits in refractory HCC. The density of CD47+macrophages analyzed by AI is higher in CBR patients. Clinical trial information: NCT05276310 . [Table: see text]