bluuebunny/crossref_metadata_2025 huggingface dataset:
Space–time clusters and co-occurrence of Plasmodium vivax and Plasmodium falciparum malaria in West Bengal, India
Authors: Maiti Meghna , Roy Utpal
Published: June 2024

Background

Malaria, a prominent vector borne disease causing over a million annual cases worldwide, predominantly affects vulnerable populations in the least developed regions. Despite their preventable and treatable nature, malaria remains a global public health concern. In the last decade, India has faced a significant decline in malaria morbidity and mortality. As India pledged to eliminate malaria by 2030, this study examined a decade of surveillance data to uncover space–time clustering and seasonal trends of Plasmodium vivax and Plasmodium falciparum malaria cases in West Bengal.

Methods

Seasonal and trend decomposition using Loess (STL) was applied to detect seasonal trend and anomaly of the time series. Univariate and multivariate space–time cluster analysis of both malaria cases were performed at block level using Kulldorff’s space–time scan statistics from April 2011 to March 2021 to detect statistically significant space–time clusters.

Results

From the time series decomposition, a clear seasonal pattern is visible for both malaria cases. Statistical analysis indicated considerable high-risk P. vivax clusters, particularly in the northern, central, and lower Gangetic areas. Whereas, P. falciparum was concentrated in the western region with a significant recent transmission towards the lower Gangetic plain. From the multivariate space–time scan statistics, the co-occurrence of both cases were detected with four significant clusters, which signifies the regions experiencing a greater burden of malaria cases.

Conclusions

Seasonal trends from the time series decomposition analysis show a gradual decline for both P. vivax and P. falciparum cases in West Bengal. The space–time scan statistics identified high-risk blocks for P. vivax and P. falciparum malaria and its co-occurrence. Both malaria types exhibit significant spatiotemporal variations over the study area. Identifying emerging high-risk areas of P. falciparum malaria over the Gangetic belt indicates the need for more research for its spatial shifting. Addressing the drivers of malaria transmission in these diverse clusters demands regional cooperation and strategic strategies, crucial steps towards overcoming the final obstacles in malaria eradication.
Effects of DASH diet with or without time-restricted eating in the management of stage 1 primary hypertension: a randomized controlled trial
Authors: Zhou Xiaoxin , Lin Xiaoqian , Yu Jing , Yang Yi , Muzammel Hira , Amissi Said , Schini-Kerth Valérie B. , Lei Xun , Jose Pedro A. , Yang Jian , Shi Dan
Published: June 2024

Background

Time-restricted eating (TRE), a popular form of intermittent fasting, has shown benefits for improving metabolic diseases and cardiometabolic health. However, the effect of TRE in the regulation of blood pressure in primary hypertension remains unclear.

Methods

A 6-week randomized controlled trial was conducted, in which a total of 74 stage 1 primary hypertensive patients without high-risk were randomly assigned to Dietary Approaches to Stop Hypertension (DASH) group (n = 37) or DASH + TRE group (n = 37). Participants in the DASH + TRE group were instructed to consume their food within an 8-h window. Scientific research platform in We Chat application was used to track participants. The primary outcome was blood pressure. The secondary outcomes included body composition, cardiometabolic risk factors, inflammation-related parameters, urinary Na+ excretion, other clinical variables and safety outcomes.

Results

The reduction of systolic blood pressure and diastolic blood pressure were 5.595 ± 4.072 and 5.351 ± 5.643 mm Hg in the DASH group and 8.459 ± 4.260 and 9.459 ± 4.375 mm Hg in the DASH + TRE group. DASH + TRE group improved blood pressure diurnal rhythm. Subjects in DASH + TRE group had decreased extracellular water and increased urinary Na+ excretion. Furthermore, the decrease in blood pressure was associated with a reduction of extracellular water or increase in urinary Na+ excretion. In addition, safety outcomes such as nighttime hunger were also reported.

Conclusion

Our study demonstrated that 8-h TRE + DASH diet caused a greater decrease in blood pressure in stage 1 primary hypertensive patients than DASH diet. This study may provide novel insights into the benefits of lifestyle modification in the treatment of primary hypertension.

Trial registration

https://www.chictr.org.cn/ (ChiCTR2300069393, registered on March 15, 2023).
Automated diagnosis of schizophrenia based on spatial–temporal residual graph convolutional network
Authors: Xu Xinyi , Zhu Geng , Li Bin , Lin Ping , Li Xiaoou , Wang Zhen
Published: June 2024

Background

Schizophrenia (SZ), a psychiatric disorder for which there is no precise diagnosis, has had a serious impact on the quality of human life and social activities for many years. Therefore, an advanced approach for accurate treatment is required.

New method

In this study, we provide a classification approach for SZ patients based on a spatial–temporal residual graph convolutional neural network (STRGCN). The model primarily collects spatial frequency features and temporal frequency features by spatial graph convolution and single-channel temporal convolution, respectively, and blends them both for the classification learning, in contrast to traditional approaches that only evaluate temporal frequency information in EEG and disregard spatial frequency features across brain regions.

Results

We conducted extensive experiments on the publicly available dataset Zenodo and our own collected dataset. The classification accuracy of the two datasets on our proposed method reached 96.32% and 85.44%, respectively. In the experiment, the dataset using delta has the best classification performance in the sub-bands.

Comparison with existing methods

Other methods mainly rely on deep learning models dominated by convolutional neural networks and long and short time memory networks, lacking exploration of the functional connections between channels. In contrast, the present method can treat the EEG signal as a graph and integrate and analyze the temporal frequency and spatial frequency features in the EEG signal.

Conclusion

We provide an approach to not only performs better than other classic machine learning and deep learning algorithms on the dataset we used in diagnosing schizophrenia, but also understand the effects of schizophrenia on brain network features.
An in-vitro three-dimensional surgical simulation technique to predict tibial tunnel length in transtibial posterior cruciate ligament reconstruction
Authors: Jia Gengxin , Jia Xiaoyang , Qiang Minfei , Shi Tianhao , Han Qinghui , Chen Yanxi
Published: June 2024

Background

During the transtibial posterior cruciate ligament (PCL) reconstruction, drilling depth excessively longer than the tibial tunnel length (TTL) is an important reason to cause popliteal neurovascular bundle injury when preparing the tibial tunnel. This study aims to develop an in-vitro three-dimensional surgical simulation technique to determine the TTL in anteromedial (AM) and anterolateral (AL) approaches.

Methods

A total of 63 knees’ 3-dimensional (3D) computed tomography models were included in this study. The SuperImage system was used to reconstruct the 3D knee model and locate the tibial PCL site. The established 3D knee model and the coordinates of the tibial PCL site were imported into Rhinoceros 3D modeling software to simulate AM and AL tibial tunnel approaches with different tibial tunnel angles (TTA). The TTL and the tibial tunnel height (TTH) were measured in this study.

Results

In AM and AL tibial tunnel approaches, the TTL showed a strong correlation with the TTA (for AM: r = 0.758, p < 0.001; for AL: r = 0.727, p < 0.001). The best fit equation to calculate the TTL based on the TTA was Y = 1.04X + 14.96 for males in AM approach, Y = 0.93X + 17.76 for males in AL approach, Y = 0.92X + 14.4 for females in AM approach, and Y = 0.94X + 10.5 for females in AL approach.

Conclusion

Marking the TTL on the guide pin or reamer could help to avoid the drill bit over-penetrated into the popliteal space to damage the neurovascular structure.
Using an intersectionality lens to explore barriers and enablers to hepatitis C point-of-care testing: a qualitative study among people who inject drugs and service providers
Authors: Fontaine Guillaume , Presseau Justin , Bruneau Julie , Etherington Cole , Thomas Isabella M. , Hung Jui-Hsia Cleo , van Allen Zack , Patey Andrea M. , Kareem Ayesha , Mortazhejri Sameh , Høj Stine Bordier , Boyer-Legault Geneviève , Grimshaw Jeremy M.
Published: June 2024

Background

Hepatitis C virus (HCV) infection is a significant global health burden, particularly among people who inject drugs. Rapid point-of-care HCV testing has emerged as a promising approach to improve HCV detection and linkage to care in harm reduction organizations such as needle and syringe programs. The objective of this study was to use an intersectionality lens to explore the barriers and enablers to point-of-care HCV testing in a needle and syringe program.

Methods

A qualitative study was conducted using semi-structured interviews with clients (people who inject drugs) and service providers in a large community organization focused on the prevention of sexually transmitted and blood borne infections and harm reduction in Montreal, Canada. An intersectionality lens was used alongside the Theoretical Domains Framework to guide the formulation of research questions as well as data collection, analysis, and interpretation.

Results

We interviewed 27 participants (15 clients, 12 providers). For clients, four themes emerged: (1) understanding and perceptions of HCV testing, (2) the role of an accessible and inclusive environment, (3) the interplay of emotions and motivations in decision-making, and (4) the impact of intersectional stigma related to HCV, behaviors, and identities. For providers, five themes emerged: (1) knowledge, skills, and confidence for HCV testing, (2) professional roles and their intersection with identity and lived experience, (3) resources and integration of services, (4) social and emotional factors, and (5) behavioral regulation and incentives for HCV testing. Intersectional stigma amplified access, emotional and informational barriers to HCV care for clients. In contrast, identity and lived experience acted as powerful enablers for providers in the provision of HCV care.

Conclusion

The application of an intersectionality lens provides a nuanced understanding of multilevel barriers and enablers to point-of-care HCV testing. Findings underscore the need for tailored strategies that address stigma, improve provider roles and communication, and foster an inclusive environment for equitable HCV care. Using an intersectionality lens in implementation research can offer valuable insights, guiding the design of equity-focused implementation strategies.
Chiral MoS2@BC fibrous membranes selectively promote peripheral nerve regeneration
Authors: Li Mengru , Li Xiao , Lv Yaowei , Yan Hede , Wang Xiang-Yang , He Jin , Zhou Chao , Ouyang Yuanming
Published: June 2024

Background

Molybdenum disulfide (MoS2) has excellent physical and chemical properties. Further, chiral MoS2 (CMS) exhibits excellent chiroptical and enantioselective effects, and the enantioselective properties of CMS have been studied for the treatment of neurodegenerative diseases. Intriguingly, left- and right-handed materials have different effects on promoting the differentiation of neural stem cells into neurons. However, the effect of the enantioselectivity of chiral materials on peripheral nerve regeneration remains unclear.

Methods

In this study, CMS@bacterial cellulose (BC) scaffolds were fabricated using a hydrothermal approach. The CMS@BC films synthesized with L-2-amino-3-phenyl-1-propanol was defined as L-CMS. The CMS@BC films synthesized with D-2-amino-3-phenyl-1-propanol was defined as D-CMS. The biocompatibility of CMS@BC scaffolds and their effect on Schwann cells (SCs) were validated by cellular experiments. In addition, these scaffolds were implanted in rat sciatic nerve defect sites for three months.

Results

These chiral scaffolds displayed high hydrophilicity, good mechanical properties, and low cytotoxicity. Further, we found that the L-CMS scaffolds were superior to the D-CMS scaffolds in promoting SCs proliferation. After three months, the scaffolds showed good biocompatibility in vivo, and the nerve conducting velocities of the L-CMS and D-CMS scaffolds were 51.2 m/s and 26.8 m/s, respectively. The L-CMS scaffolds showed a better regenerative effect than the D-CMS scaffolds. Similarly, the sciatic nerve function index and effects on the motor and electrophysiological functions were higher for the L-CMS scaffolds than the D-CMS scaffolds. Finally, the axon diameter and myelin sheath thickness of the regenerated nerves were improved in the L-CMS group.

Conclusion

We found that the CMS@BC can promote peripheral nerve regeneration, and in general, the L-CMS group exhibited superior repair performance. Overall, the findings of this study reveal that CMS@BC can be used as a chiral nanomaterial nerve scaffold for peripheral nerve repair.

Graphical Abstract
Possible association of dose rate and the development of late visual toxicity for patients with intracranial tumours treated with pencil beam scanned proton therapy
Authors: Meijers Arturs , Daartz Juliane , Knopf Antje-Christin , van Heerden Michelle , Bizzocchi Nicola , Vazquez Miriam Varela , Bachtiary Barbara , Pica Alessia , Shih Helen A , Weber Damien Charles
Published: June 2024

Background and purpose

Rare but severe toxicities of the optic apparatus have been observed after treatment of intracranial tumours with proton therapy. Some adverse events have occurred at unusually low dose levels and are thus difficult to understand considering dose metrics only. When transitioning from double scattering to pencil beam scanning, little consideration was given to increased dose rates observed with the latter delivery paradigm. We explored if dose rate related metrics could provide additional predicting factors for the development of late visual toxicities.

Materials and methods

Radiation-induced intracranial visual pathway lesions were delineated on MRI for all index cases. Voxel-wise maximum dose rate (MDR) was calculated for 2 patients with observed optic nerve toxicities (CTCAE grade 3 and 4), and 6 similar control cases. Additionally, linear energy transfer (LET) related dose enhancing metrics were investigated.

Results

For the index cases, which developed toxicities at low dose levels (mean, 50 GyRBE), some dose was delivered at higher instantaneous dose rates. While optic structures of non-toxicity cases were exposed to dose rates of up to 1 to 3.2 GyRBE/s, the pre-chiasmatic optic nerves of the 2 toxicity cases were exposed to dose rates above 3.7 GyRBE/s. LET-related metrics were not substantially different between the index and non-toxicity cases.

Conclusions

Our observations reveal large variations in instantaneous dose rates experienced by different volumes within our patient cohort, even when considering the same indications and beam arrangement. High dose rate regions are spatially overlapping with the radiation induced toxicity areas in the follow up images. At this point, it is not feasible to establish causality between exposure to high dose rates and the development of late optic apparatus toxicities due to the low incidence of injury.
Association of early menarche with breast tumor molecular features and recurrence
Authors: Harris Alexandra R. , Wang Tengteng , Heng Yujing J. , Baker Gabrielle M. , Le Phuong Anh , Wang Jun , Ambrosone Christine , Brufsky Adam , Couch Fergus J. , Modugno Francesmary , Scott Christopher G. , Vachon Celine M. , Hankinson Susan E. , Rosner Bernard A. , Tamimi Rulla M. , Peng Cheng , Eliassen A. Heather
Published: June 2024

Background

Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear.

Methods

We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses’ Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952).

Results

Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN$$\alpha$$
α
and IFN$$\gamma$$
γ
). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (β = 0.082 [0.02–0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18–2.85] and HER2-enriched, OR = 2.32 [1.46–3.69]), and PAM50 risk of recurrence score (β = 4.81 [1.71–7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10–2.25]).

Conclusions

Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.
Circulating TMAO, the gut microbiome and cardiometabolic disease risk: an exploration in key precursor disorders
Authors: Naghipour Saba , Cox Amanda J. , Fisher Joshua J. , Plan Manuel , Stark Terra , West Nic , Peart Jason N. , Headrick John P. , Du Toit Eugene F.
Published: June 2024

Background

Elevations in the gut metabolite trimethylamine-N-oxide (TMAO) have been linked to cardiovascular and metabolic diseases. Whether elevated TMAO levels reflect early mechanistic involvement or a sequela of evolving disease awaits elucidation. The purpose of this study was to further explore these potential associations.

Methods

We investigated relationships between circulating levels of TMAO and its pre-cursor substrates, dietary factors, gut microbiome profiles and disease risk in individuals with a Healthy BMI (18.5 < BMI < 25, n = 41) or key precursor states for cardiometabolic disease: Overweight (25 < BMI < 30 kg/m2, n = 33), Obese (BMI > 30, n = 27) and Metabolic Syndrome (MetS; ≥ 3 ATPIII report criteria, n = 39).

Results

Unexpectedly, plasma [TMAO] did not vary substantially between groups (means of 3–4 µM; p > 0.05), although carnitine was elevated in participants with MetS. Gut microbial diversity and Firmicutes were also significantly reduced in the MetS group (p < 0.05). Exploratory analysis across diverse parameters reveals significant correlations between circulating [TMAO] and seafood intake (p = 0.007), gut microbial diversity (p = 0.017–0.048), and plasma [trimethylamine] (TMA; p = 0.001). No associations were evident with anthropometric parameters or cardiometabolic disease risk. Most variance in [TMAO] within and between groups remained unexplained.

Conclusions

Data indicate that circulating [TMAO] may be significantly linked to seafood intake, levels of TMA substrate and gut microbial diversity across healthy and early disease phenotypes. However, mean concentrations remain < 5 µM, with little evidence of links between TMAO and cardiometabolic disease risk. These observations suggest circulating TMAO may not participate mechanistically in cardiometabolic disease development, with later elevations likely a detrimental sequela of extant disease.
Evaluation of [11C]UCB-A positron emission tomography in human brains
Authors: Xiong Mengfei , Lubberink Mark , Appel Lieuwe , Fang Xiaotian Tsong , Danfors Torsten , Kumlien Eva , Antoni Gunnar
Published: June 2024

Background

In preclinical studies, the positron emission tomography (PET) imaging with [11C]UCB-A provided promising results for imaging synaptic vesicle protein 2A (SV2A) as a proxy for synaptic density. This paper reports the first-in-human [11C]UCB-A PET study to characterise its kinetics in healthy subjects and further evaluate SV2A-specific binding.

Results

Twelve healthy subjects underwent 90-min baseline [11C]UCB-A scans with PET/MRI, with two subjects participating in an additional blocking scan with the same scanning procedure after a single dose of levetiracetam (1500 mg). Our results indicated abundant [11C]UCB-A brain uptake across all cortical regions, with slow elimination. Kinetic modelling of [11C]UCB-A PET using various compartment models suggested that the irreversible two-tissue compartment model best describes the kinetics of the radioactive tracer. Accordingly, the Patlak graphical analysis was used to simplify the analysis. The estimated SV2A occupancy determined by the Lassen plot was around 66%. Significant specific binding at baseline and comparable binding reduction as grey matter precludes the use of centrum semiovale as reference tissue.

Conclusions

[11C]UCB-A PET imaging enables quantifying SV2A in vivo. However, its slow kinetics require a long scan duration, which is impractical with the short half-life of carbon-11. Consequently, the slow kinetics and complicated quantification methods may restrict its use in humans.
Improving the learning-teaching process through adaptive learning strategy
Authors: Rincon-Flores Elvira G. , Castano Leticia , Guerrero Solis Sadie Lissette , Olmos Lopez Omar , Rodríguez Hernández Carlos Felipe , Castillo Lara Laura Angélica , Aldape Valdés Laura Patricia
Published: June 2024

Much has been written about Adaptive Learning, but does its implementation alone guarantee success? We have found that integrating an Adaptive Learning Strategy with diverse didactic techniques gives better results. The objectives of this exploratory study were to know the impact of the Adaptive Learning Strategy on students’ learning and achievement of disciplinary and transversal sub-competencies in courses supported by an Adaptive Platform in the School of Engineering and Sciences at Tecnologico de Monterrey. The assessment of the students’ and professors’ experience with an Adaptive Learning Strategy evaluated platform’s usability, teaching, learning, and engagement. The study employed a mixed methodological approach, sequential Quant- > Qual, and was quasi-experimental, with control and experimental groups. The courses that participated in the intervention were Computational Thinking, Physics I, Physics II, and Fundamental Mathematical Modeling. The findings indicated that implementing an innovation like Adaptive Learning positively impacts students’ learning and improvement when integrating elements of a flipped classroom, self-regulated learning, and micro-learning into an Adaptive Learning Strategy. The authors also propose an Implementation Model of the Adaptive Learning Strategy that has been designed by the university, implemented, and evaluated successfully.
Influence of surface and material technologies on the loss of lubrication performance of gears
Authors: Morhard B. , Lohner T. , Stahl K.
Published: June 2024

Enabling gears to withstand loss of lubrication in gearboxes without secondary oil supply systems can reduce weight and space demand and thus fuel consumption. This study investigates the potential of surface and material technologies on the loss of lubrication performance of gears. Thereby, superfinished, coated, and nitrided gears are compared to ground gears. Systematic experiments under loss of lubrication are performed at a back-to-back gear test rig with circumferential speeds of up to 20 m/s and Hertzian pressures in the pitch point of up to 1723 N/mm2. Torque loss, pinion bulk temperatures, and tooth flank surface are analyzed. The results show that surface and material technologies can greatly influence frictional behavior and damage initiation of gears operating under loss of lubrication. With the materials and conditions tested, superfinishing yields to accelerated rise of frictional losses and thus scuffing. Coatings lead to significantly enhanced service life under loss of lubrication by friction reduction and scuffing avoidance.
Potentiating effect of AMD3100 on bone morphogenetic protein-2 induced bone regeneration
Authors: Shim Gyu-Jo , Lee Chung O. , Lee Jung-Tae , Jung Hong-Moon , Kwon Tae-Geon
Published: June 2024

Background

AMD3100, a CXCR4 antagonist, is currently prescribed for activating the mobilization of hematopoietic stem cells. Recently, AMD3100 was shown to potentiate bone morphogenetic protein-2 (BMP-2)-induced bone formation by stimulating the trafficking of mesenchymal cells. However, optimization of the strategic combination of AMD3100 and BMP-2 has not yet been clearly established. The purpose of this study was to evaluate the effect of AMD3100 on BMP-2-induced bone regeneration in vitro and in a mouse calvarial defect healing model.

Methods

In vitro osteoblastic differentiation and cell migration after sequential treatments with AMD3100 and BMP-2 were analyzed by alkaline phosphatase (ALP) activity, ALP staining, and calcium accumulation. Migration capacity was evaluated after treating mesenchymal cells with AMD3100 and/or BMP-2. A critical-size calvarial defect model was used to evaluate bone formation after sequential or continuous treatment with AMD3100 and BMP-2. The degree of bone formation in the defect was analyzed using micro-computed tomography (micro-CT) and histological staining.

Results

Compared with single treatment using either AMD3100 or BMP-2 alone, sequential treatment with AMD3100 followed by BMP-2 on mesenchymal cells increased osteogenic differentiation. Application of AMD3100 and subsequent BMP-2 significantly activated cell migration on mesenchymal cell than BMP-2 alone or AMD3100 alone.

Micro-CT and histomorphometric analysis showed that continuous intraperitoneal (IP) injection of AMD3100 resulted significantly increased new bone formation in BMP-2 loaded scaffold in calvarial defect than control groups without AMD3100 IP injection. Additionally, both single IP injection of AMD3100 and subsequent BMP-2 injection to the scaffold in calvarial defect showed pronounced new bone formation compared to continuous BMP-2 treatment without AMD3100 treatment.

Conclusion

Our data suggest that single or continuous injection of AMD3100 can potentiate BMP-2-induced osteoblastic differentiation and bone regeneration. This strategic combination of AMD3100 and BMP-2 may be a promising therapy for bone regeneration.
Association of VEGF-2549I/D promoter polymorphism with gastrointestinal tract cancer risk: a meta-analysis
Authors: Mahajan Deepanshi , Sambyal Vasudha , Guleria Kamlesh
Published: June 2024

Background

Gastrointestinal tract (GIT) cancers are complex disorders affecting millions of people worldwide. The vascular endothelial growth factor (VEGF) helps in the development of different GIT cancers by promoting abnormal angiogenesis in cancer cells. The role of VEGF-2549I/D polymorphism in influencing GIT cancer susceptibility has been studied in different populations with inconclusive results. Therefore, the relationship between VEGF-2549I/D polymorphism with GIT susceptibility was studied by performing a meta-analysis study.

Methods

Various online databases were used for identifying the articles. Based on study selection criteria, five studies on different GIT cancers including 1178 patients and 1520 controls were included in the meta-analysis. The accuracy of the study results was determined by performing a trial sequential analysis.

Results

In this study, the VEGF-2549I/D polymorphism did not influence the GIT cancer susceptibility in the overall analysis as well as when stratified according to ethnicity (p > 0.05). Stratification of all the studies based on the different GIT cancers reported an increased susceptibility to gastric cancer under different genetic models including allele contrast (OR = 1.67, CI = 1.294–2.157, p = 0.00008), recessive (OR = 1.68, CI = 1.056–2.660, p = 0.029), dominant (OR = 2.49, CI = 1.617–3.823, p = 0.00003), over-dominant (OR = 1.52, CI = 1.055–2.177, p = 0.025), II vs DD (OR = 2.97, CI = 1.692–5.208, p = 0.00015) and ID vs DD model (OR = 2.35, CI = 1.501–3.669, p = 0.00018).

Conclusion

There was no relationship between VEGF-2549I/D promoter polymorphism and GIT cancer susceptibility in the overall population and also in different ethnic groups. Stratification analysis revealed higher susceptibility towards gastric cancer development with VEGF-2549I/D polymorphism.
Efficiency assessment of a two-stage diagnostic strategy combining CT angiography and fractional flow reserve derived from coronary CT angiography for the detection of myocardial ischemia: a simulation study
Authors: Iwata Kunihiro , Yanagisawa Akira , Ogasawara Katsuhiko
Published: June 2024

Background

The importance of a diagnostic strategy combining coronary computed tomography angiography (CCTA) with fractional flow reserve derived from CCTA (FFRCT) for detecting myocardial ischemia is increasing. However, sensitivity and specificity alone may be insufficient to understand the efficiency characteristics of a diagnostic strategy combining CCTA and FFRCT (DSCCF). Our study aimed to evaluate the overall efficiency of DSCCF in detecting myocardial ischemia and compare it with other diagnostic strategies to determine whether evaluation by DSCCF is currently appropriate.

Results

This simulation study included 1000 patients with stable chest pain and suspected myocardial ischemia. Using a decision tree analysis, assuming a diagnostic strategy of adding FFRCT to CCTA-positive patients, we calculated the following efficiency parameters of DSCCF: (1) true positive (TP), false positive (FP), net false negative (FN), and net true negative (TN) test results; (2) net sensitivity; (3) net specificity; (4) positive predictive value; (5) negative predictive value; (6) post-test probability; (7) diagnostic accuracy; (8) diagnostic odds ratio; and (9) number needed to diagnose. We also calculated the efficiency parameters of other diagnostic strategies and compared them with those of DSCCF. In the basic setting, regarding efficiency parameters (1), the number of TPs, FPs, net FNs, and net TNs were 254, 69, 46, and 631, respectively. Efficiency parameters (2)–(9) were 0.85 (95% confidence interval [CI], 0.80–0.89), 0.90 (95% CI 0.88–0.92), 0.79 (95% CI 0.74–0.83), 0.93 (95% CI 0.91–0.95), 0.07 (95% CI 0.05–0.09), 0.89 (95% CI 0.86–0.90), 50.50 (95% CI 33.83–75.37), and 1.34 (95% CI 1.24–1.48), respectively. Compared with other diagnostic strategies, DSCCF had good efficiency parameters. Moreover, the sensitivity analysis did not reveal any evidence to contradict the findings in the basic setting.

Conclusions

This study demonstrated the diagnostic ability characteristics of DSCCF by assessing various efficiency parameters. Compared with other diagnostic strategies, DSCCF had good efficiency. In terms of efficiency, evaluation using DSCCF for detecting myocardial ischemia appears to be appropriate.
Overexpression of heat shock protein 47 is associated with increased proliferation and metastasis in gastric cancer
Authors: Lee Jieun , Hwang Jung-Ah , Hong Seung-Hyun , Kim Seon-Young , Seol Donghyeok , Choi Il Ju , Lee Yeon-Su
Published: June 2024

Here, we investigated that the heat shock protein 47 (HSP47) plays a crucial role in the progression of gastric cancer (GC). We analyzed HSP47 gene expression in GC cell lines and patient tissues. The HSP47 mRNA and protein expression levels were significantly higher in GC cell lines and tumor tissues compared to normal gastric mucosa. Using siRNA to silence the expression of HSP47 in GC cells resulted in a significant reduction in their proliferation, wound healing, migration, and invasion capacities. Additionally, we also showed that the mRNA expression of matrix metallopeptidase-7 (MMP-7), a metastasis-promoting gene, was significantly reduced in HSP47 siRNA-transfected GC cells. We confirmed that the HSP47 promoter region was methylated in the SNU-216 GC cell line expressing low levels of HSP47 and in most non-cancerous gastric tissues. It means that the expression of HSP47 is regulated by epigenetic regulatory mechanisms. These findings suggest that targeting HSP47, potentially through its promoter methylation, could be a useful new therapeutic strategy for treating GC.
Extracting Systemic Anticancer Therapy and Response Information From Clinical Notes Following the RECIST Definition
Authors: Zuo Xu , Kumar Ashok , Shen Shuhan , Li Jianfu , Cong Grace , Jin Edward , Chen Qingxia , Warner Jeremy L. , Yang Ping , Xu Hua
Published: June 2024

PURPOSE

The RECIST guidelines provide a standardized approach for evaluating the response of cancer to treatment, allowing for consistent comparison of treatment efficacy across different therapies and patients. However, collecting such information from electronic health records manually can be extremely labor-intensive and time-consuming because of the complexity and volume of clinical notes. The aim of this study is to apply natural language processing (NLP) techniques to automate this process, minimizing manual data collection efforts, and improving the consistency and reliability of the results.

METHODS

We proposed a complex, hybrid NLP system that automates the process of extracting, linking, and summarizing anticancer therapy and associated RECIST-like responses from narrative clinical text. The system consists of multiple machine learning–/deep learning–based and rule-based modules for diverse NLP tasks such as named entity recognition, assertion classification, relation extraction, and text normalization, to address different challenges associated with anticancer therapy and response information extraction. We then evaluated the system performances on two independent test sets from different institutions to demonstrate its effectiveness and generalizability.

RESULTS

The system used domain-specific language models, BioBERT and BioClinicalBERT, for high-performance therapy mentions identification and RECIST responses extraction and categorization. The best-performing model achieved a 0.66 score in linking therapy and RECIST response mentions, with end-to-end performance peaking at 0.74 after relation normalization, indicating substantial efficacy with room for improvement.

CONCLUSION

We developed, implemented, and tested an information extraction system from clinical notes for cancer treatment and efficacy assessment information. We expect this system will support future cancer research, particularly oncologic studies that focus on efficiently assessing the effectiveness and reliability of cancer therapeutics.
Updated safety and efficacy data of combined KRAS G12C inhibitor (glecirasib, JAB-21822) and SHP2 inhibitor (JAB-3312) in patients with KRAS p.G12C mutated solid tumors.
Authors: Zhao Jun , Fang Jian , Yu Yan , Chu Qian , Li Xiaoyan , Chen Jiayan , Liu Zhe , Zhang Li , Wu Lin , Zhuang Wu , Li XingYa , Zhao Yanqiu , Xing Ligang , Liu Lian , Bai Chunmei , Dong Xiaorong , Song Qibin , Pan Pinghua , Fang Xuefeng , Wang Jie
Published: June 2024

3008

Background: Resistance to KRAS G12C inhibitor in non-small cell lung cancer (NSCLC) can be overcome by SHP2 blockade. This concept was tested in Phase I study of glecirasib combined with JAB-3312 in patients (pts) with KRAS p.G12C mutated tumors. Promising preliminary data of safety and response were reported at the 2023 ESMO (653O). Here, we present the updated safety and efficacy data with treatment response and progression-free survival (PFS) of the combination therapy in front-line NSCLC. Methods: The phase 1/2a study [NCT05288205] evaluated glecirasib plus JAB-3312 in patients with KRAS p.G12C mutated solid tumors. The primary objective of the dose-escalation phase was to assess the safety and tolerability of the combination therapy, and the primary objective of the dose-expansion phase was to assess efficacy. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), PFS by investigator per RECIST1.1 and overall survival. Glecirasib 400 mg or 800 mg daily was combined with various JAB-3312 doses and schedules. Results: As of December 1st, 2023, 179 pts were enrolled, including 157 with NSCLC, 17 with colorectal cancer, and five with other tumor types. Treatment-related adverse events (TRAE) ≥ grade 3 occurred in 41.9% of all pts. There were no treatment-related deaths. Discontinuation of either glecirasib or JAB-3312 due to TRAE occurred in 7.8% of all pts. The AE profile was unchanged from the last ESMO report. The most common ( > 20%) TRAEs included anemia, ALT/AST increased, hypertriglyceridemia, bilirubin increased, neutropenia/leukopenia, creatine kinase increased, and edema. No overlapped toxicity was observed for this combination therapy. Amongst all pts enrolled, 88 had NSCLC and received the combination therapy as front-line treatment in seven dosing groups. The median follow-up duration was 6.1 (range:0.5-16.7) months. Eighty pts had at least once post-treatment efficacy assessment. The ORR was 72.5% (58/80) and DCR was 96.3% (77/80). In the group of glecirasib 800mg QD + JAB-3312 2mg one week on/one week off, the ORR was 77.8% (21/27) and DCR was 92.6% (25/27). The median PFS was not mature by the data cut-off date. The 6-month and 12-month PFS rate were 67.3% and 53.7%, respectively. Additional safety and efficacy data will be presented at the meeting. Conclusions: Glecirasib plus JAB-3312 has a manageable safety profile and a promising ORR and PFS as a front-line treatment for patients with KRAS p.G12C NSCLC. This combination will be further evaluated in a randomized phase III trial in NSCLC. Clinical trial information: NCT05288205 .
Ipatasertib in patients with AKT1/2/3 mutation-positive (AKTmut) tumors: TAPISTRY study.
Authors: Thomas David Morgan , Daniele Gennaro , Kim Jeong Eun , Gadgeel Shirish M. , Ahn Eugene R. , Paz-Ares Luis G. , Prenen Hans , Chen David , Fang Junhan , Wilson Timothy R. , Simmons Brian P. , Barlesi Fabrice
Published: June 2024

3092

Background: AKT1/2/3 point mutations are found in ~1% of all solid tumors, with varying prevalence across different tumor types. Ipatasertib is an inhibitor of the AKT kinase, but its antitumor activity as monotherapy in patients with AKTmut tumors is unknown. We present efficacy and safety data of ipatasertib in patients with advanced/metastatic AKTmut solid tumors from Cohort E of the TAPISTRY trial (NCT04589845). Methods: TAPISTRY is a phase II, global, open-label, multi-cohort trial evaluating the efficacy and safety of different therapies in patients with advanced/metastatic solid tumors. Patients in Cohort E were aged ≥12 years and had solid tumors harboring an AKT1/2/3mutation identified by next-generation sequencing and measurable disease by RECIST v1.1. Oral ipatasertib 400 mg was administered once daily. Tumor assessments were performed at screening, every eight weeks from Day 1/Cycle 1 for one year, and every 12 weeks after that. The primary endpoint was objective response rate (ORR) by independent review committee (IRC). Key secondary endpoints included ORR by investigator, duration of response, progression-free survival, overall survival and safety. Results: At data cut-off (16 Jul 2023), 50 patients were safety evaluable and 48 were efficacy evaluable. In the safety-evaluable population, median age was 59 years (range, 30–79); 98% of patients (n/N = 49/50) had an AKT1 mutation ( AKT1 E17K, n=47) and 2% (n/N = 1/50) had an AKT2 E17K mutation; 41/50 patients (82%) had received ≥2 prior lines of treatment. Efficacy-evaluable patients had 10 different tumor types, the most common being breast cancer (n/N = 21/48; 44%). Key outcomes are summarized in the Table. After a median follow-up of 11.3 months, ORR by IRC in efficacy-evaluable patients was 31.3% (n/N = 15/48; 95% CI 18.7–46.3), driven by responses in three tumor types: breast (n/N = 7/21; 33%), endometrial (n/N = 7/7; 100%), and head and neck (n/N = 1/2; 50%). The most frequent adverse event was diarrhea (n/N = 39/50; 78%). Safety was consistent with the known profile of ipatasertib; no new safety signals were identified. Conclusions: Treatment with ipatasertib led to a marked and durable antitumor activity in some tumor types such as endometrial cancer, but not in the overall tumor-agnostic cohort. Further studies are needed to understand the relevance of AKT inhibition in these tumor types. Clinical trial information: NCT04589845 . [Table: see text]
FCN-159, a MEK1/2 inhibitor, in patients with advanced melanoma harboring NRAS or NF1mutations: A phase 1B dose-expansion study.
Authors: Gu Junjie , Mao Lili , Guo Jun , Jiang Yu , Zhu Lingjun , Zhang Xiaoshi , Yan Wangjun , Chen Yu , Tan Chang , Zhu Weiyou , Zhang Jian , Liu Jie , Lin Jing , Wu Zhuli , Wang Xingli , Yang Yuchen , Li Ben , Si Lu
Published: June 2024

3095

Background: In phase 1A dose-escalation study, preliminary anti-tumor activity of FCN-159 was observed in advanced melanoma patients harboring NRAS mutations (ORR: 19.0%, mPFS: 3.8 months) with tolerable safety profile, which was posted during AACR 2022 (No.: 22-LB-7398-AACR). Here, we report the results from phase 1B dose-expansion study in advanced NRAS- or NF1-mutant melanoma patients at RP2D predetermined at 12 mg. Methods: This open-label, dose-expansion, phase 1B study (NCT03932253) consists of two cohorts, which enrolled patients with unresectable stage III/IV melanoma harboring NRAS or NF1 mutations, respectively. Patients received FCN-159 orally at 12 mg once daily (QD) continuously in 28-day cycles. The primary endpoint was anti-tumor activity. Results: As of July 17, 2023, 46 patients (32 patients with NRASmutations in Cohort 1 and 14 patients with NF1mutations in Cohort 2) were enrolled and received 12 mg FCN-159 QD. The median follow-up time was 8.6 months. Among 25 patients who failed in previous anti-PD-1 therapy in Cohort 1, 6 had confirmed partial responses (ORR, 24.0%; 95% confidence interval [CI], 9.4–45.1). Median DOR was 6.5 months (95% CI, 2.7–NE). Median progression-free survival (mPFS) was 3.6 months (95% CI, 1.8–5.5). Among 14 patients in Cohort 2, 1 had PR (ORR, 7.1%; 95% CI, 0.2-33.9) and mPFS was 2.8 months (95% CI, 1.8-5.5) (Table). Grade≥3 FCN-159-related treatment-emergent adverse events (TEAEs) were reported in 10 (21.7%) patients in both cohorts; the most common was blood creatine phosphokinase increased (13.0%). FCN-159–related serious AEs (SAEs) were reported in 3 (6.5%) patients, which were edema lower limb, cellulitis and pneumonia. Two (4.3%) patients discontinued treatment due to FCN-159 related TEAEs, including serous retinal detachment and herpes zoster. No FCN-159-related TEAEs led to death. Conclusions: FCN-159 showed encouraging efficacy data with well tolerated safety profile in patients with NRAS-mutant advanced melanoma, especially those who failed in previous anti-PD-1 therapy. Clinical trial information: NCT03932253 . [Table: see text]
Comprehensive characterization of ERBB2 genomic alterations inlung cancer.
Authors: El Zarif Talal , Stockhammer Paul , Schillo Jacob , Goldberg Sarah B. , Politi Katerina A. , Grant Michael J
Published: June 2024

3148

Background: ERBB2mutations () occur in 1-4% of non-small cell lung cancers (NSCLC). Trastuzumab-deruxtecan is FDA-approved for the treatment of metastatic ERBB2-mutant NSCLC based mostly on data from NSCLCs harboring tyrosine kinase domain (TKD) ERBB2mut. The genomic and clinical characteristics of NSCLC with ERBB2 mut beyond the TKD remain largely unexplored. Methods: Patients (pts) with NSCLCs with oncogenic ERBB2 mut and genomic tumor profiling data from the AACR Project GENIE database were included. The cohort was divided into pts with tumors harboring TKD, extracellular (ECD), or transmembrane (TMD) and juxtamembrane domain (JMD) ERBB2mut. Clinico-genomic characteristics were compared between the groups. The Kaplan-Meier method was used to estimate progression-free survival (PFS) with first-line systemic therapy, and log-rank tests were used for comparisons. Results: Of 483 pts with ERBB2-mutant NSCLC, 64% were female, 81% were White, and 13% were Asian. TKD, ECD, and TMD/JMD ERBB2 mut were identified in 362 (75%), 88 (18%), and 33 (7%) cases, respectively. Pts with ECD vs. TKD ERBB2mut tumors were more likely to be males (47% vs. 33%, p=0.03) and have tumors with squamous histology (7% vs. 1%, p<0.0001). Among pts with (n=39), those with ECD vs. TKD ERBB2 mut tumors were more likely to have a history of smoking (100% vs. 42%, p = 0.02). The most common TKD, ECD, and TMD/JMD ERBB2 mut were in-frame ex20ins Y772_A775dup (n=224/362, 62%), missense S310F/Y (n=45/88, 51%), and missense V659E/D (n=10/33, 30%) mut, respectively. ECD vs. TKD ERBB2-mutant tumors harbored a distinct genomic phenotype with significantly higher median tumor mutational burden (11.1 vs. 5.2 mut/Mb, p<0.003), median fraction of genome altered (0.2 vs. 0.1, p = 0.02), and rate of co-mut in EGFR (32% vs. 3.6%, p<0.0001), KRAS (17% vs. 2.5%, p<0.0001), STK11 (23% vs. 4.3%, p<0.0001), KEAP1 (23% vs 5%, p<0.0001) and SMARCA4 (19% vs 4.5%, p<0.0001). Of 343 cases with ERBB2 copy number profiling, 32 (9.3%) harbored ERBB2 amplification. ERBB2-mutant NSCLCs with vs. without ERBB2amplifications had a higher frequency of TP53 co-mut (84% vs. 48%, p <0.001). Of 39 pts with available clinical data, most had ECD (n=6) ERBB2 mut tumors and received first-line platinum-based chemotherapy (n=31). The presence of a co-mut in STK11 (HR 3.5, 0.4–27.4, p=0.03) and KEAP1 (HR 3.9, 0.7–20.6, p=0.002) conferred shorter PFS on first-line systemic therapy. Pts with ECD vs. TKD ERBB2 mut tumors had shorter PFS (HR 2.4, 95% CI 0.7–8.2, p=0.04). Conclusions: NSCLC tumors harboring ECD ERBB2 mut are associated with a distinct clinical and molecular phenotype and inferior outcomes with chemotherapy compared to pts with tumors harboring TKD mut. These findings enhance our understanding of disease heterogeneity in ERBB2-mutant NSCLC and may aid in optimizing treatment strategies for this unique population.