bluuebunny/crossref_metadata_2025 huggingface dataset:
Cumulative Distribution Function and Spatially Resolved Surface-Enhanced Raman Spectroscopy for the Quantitative Analysis of Emtricitabine
Authors: Hrncirova Jana , Butler Marguerite R. , Dutta Sucharita , Clark Meredith R. , Cooper John B.
Published: March 2024

Surface-enhanced Raman spectroscopy (SERS) has exceptional analytical sensitivity and selectivity. However, SERS irreproducibility presents an obstacle when using it for precise quantitative measurements. In this study, colloidal nanoparticles evaporated to dryness are used as a SERS active surface for the detection of the HIV drug emtricitabine (FTC; trade name Emtriva). Despite the irreproducibility of the SERS resulting from the stochastic process of evaporation, using a SERS scanning instrument, the SERS enhancement factors of spatially resolved spectra have a well-defined distribution of signals for a given analyte concentration. This distribution follows a power law function ranging from weak (very abundant signals) to very strong (sparse signals). By definition, a power law distribution cannot have a true mean. Hence a cumulative distribution function was used to model the concentration of emtricitabine, and calibration curves were constructed. For stochastically generated quantitative data sets, the precision of this approach is superior to methods utilizing signal averaging and improves analytical sensitivity.
Adjuvant chemotherapy and survival in males aged 70 years or older with breast cancer: a population-based retrospective study
Authors: Yu Yushuai , Huang Kaiyan , Liu Yushan , Chen Ruiliang , Yu Xin , Song Chuangui
Published: March 2024

Background

Male breast cancer constitutes a minority of breast cancer diagnoses, yet its incidence has been on the rise in recent decades. However, elderly male breast cancer patients have been inadequately represented in clinical trials, posing challenges in treatment decisions. This study seeks to clarify the efficacy of chemotherapy in this demographic and identify the population most likely to benefit from such intervention.

Methods

We conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database, encompassing a total of 1900 male breast cancer patients aged 70 years or older. Among them, 1652 were categorized in the no-chemotherapy group, while 248 were in the chemotherapy group. A multifactorial logistic regression model was employed to investigate the determinants influencing the administration of chemotherapy in elderly male breast cancer patients. Additionally, the multivariate Cox proportional hazards regression model was applied to identify factors associated with outcomes, with overall survival (OS) as the primary endpoint.

Results

Multivariate logistic regression analysis revealed that grade, tumor size, and nodal status were robust predictors for elderly male breast cancer patients receiving chemotherapy. Furthermore, the multivariate analysis demonstrated that chemotherapy conferred benefits compared to the no-chemotherapy group (HR = 0.822, 95% CI: 0.682–0.991, p = 0.040). Stratified analyses indicated that individuals with N+, poorly/undifferentiated grade, and stage II/III disease could derive benefits from chemotherapy. Upon further investigation of progesterone receptor (PR) positive patients, it was found that only stage III patients experienced significant benefits from chemotherapy (HR = 0.571, 95% CI: 0.372–0.875, p = 0.010). Conversely, in PR negative patients, both stage II (HR = 0.201, 95% CI: 0.051–0.792, p = 0.022) and stage III patients (HR = 0.242, 95% CI: 0.060–0.972, p = 0.046) derived benefits from chemotherapy.

Conclusion

Adjuvant chemotherapy may benefit certain elderly male breast cancer patients, specifically those with positive lymph node status, poorly/undifferentiated grade, and PR-positive in stage III, as well as PR-negative expression in stage II/III. Given favorable physical tolerance, it is advisable not to hastily dismiss chemotherapy for these elderly male breast cancer patients.
ROAR-A: re-optimization based Online Adaptive Radiotherapy of anal cancer, a prospective phase II trial protocol
Authors: Storm Katrine Smedegaard , Åström Lina M , Sibolt Patrik , Behrens Claus P , Persson Gitte F , Serup-Hansen Eva
Published: March 2024

Background

Chemo-radiotherapy with curative intent for anal cancer has high complete remission rates, but acute treatment-related gastrointestinal (GI) toxicity is significant. Toxicity occurs due to irradiation of surrounding normal tissue. Current radiotherapy requires the addition of large planning margins to the radiation field to ensure target coverage regardless of the considerable organ motion in the pelvic region. This increases the irradiated volume and radiation dose to the surrounding normal tissue and thereby toxicity. Online adaptive radiotherapy uses artificial intelligence to adjust the treatment to the anatomy of the day. This allows for the reduction of planning margins, minimizing the irradiated volume and thereby radiation to the surrounding normal tissue.This study examines if cone beam computed tomography (CBCT)-guided oART with daily automated treatment re-planning can reduce acute gastrointestinal toxicity in patients with anal cancer.

Methods/design

The study is a prospective, single-arm, phase II trial conducted at Copenhagen University Hospital, Herlev and Gentofte, Denmark. 205 patients with local only or locally advanced anal cancer, referred for radiotherapy with or without chemotherapy with curative intent, are planned for inclusion. Toxicity and quality of life are reported with Common Terminology Criteria of Adverse Events and patient-reported outcome questionnaires, before, during, and after treatment. The primary endpoint is a reduction in the incidence of acute treatment-related grade ≥ 2 diarrhea from 36 to 25% after daily online adaptive radiotherapy compared to standard radiotherapy. Secondary endpoints include all acute and late toxicity, overall survival, and reduction in treatment interruptions.

Results

Accrual began in January 2022 and is expected to finish in January 2026. Primary endpoint results are expected to be available in April 2026.

Discussion

This is the first study utilizing online adaptive radiotherapy to treat anal cancer. We hope to determine whether there is a clinical benefit for the patients, with significant reductions in acute GI toxicity without compromising treatment efficacy.

Trial registration

ClinicalTrials.gov Identifier: NCT05438836. Danish Ethical Committee: H-21028093
Accuracy of endometrial sampling in the diagnosis of endometrial cancer: a multicenter retrospective analysis of the JAGO-NOGGO
Authors: Alwafai Zaher , Beck Maximilian Heinz , Fazeli Sepideh , Gürtler Kathleen , Kunz Christine , Singhartinger Juliane , Trojnarska Dominika , Zocholl Dario , Krankenberg David Johannes , Blohmer Jens-Uwe , Sehouli Jalid , Pietzner Klaus
Published: March 2024

Background

Accurate preoperative molecular and histological risk stratification is essential for effective treatment planning in endometrial cancer. However, inconsistencies between pre- and postoperative tumor histology have been reported in previous studies. To address this issue and identify risk factors related to inaccurate histologic diagnosis after preoperative endometrial evaluation, we conducted this retrospective analysis.

Methods

We conducted a retrospective analysis involving 375 patients treated for primary endometrial cancer in five different gynaecological departments in Germany. Histological assessments of curettage and hysterectomy specimens were collected and evaluated.

Results

Preoperative histologic subtype was confirmed in 89.5% of cases and preoperative tumor grading in 75.2% of cases. Higher rates of histologic subtype variations (36.84%) were observed for non-endometrioid carcinomas. Non-endometrioid (OR 4.41) histology and high-grade (OR 8.37) carcinomas were identified as predictors of diverging histologic subtypes, while intermediate (OR 5.04) and high grading (OR 3.94) predicted diverging tumor grading.

Conclusion

When planning therapy for endometrial cancer, the limited accuracy of endometrial sampling, especially in case of non-endometrioid histology or high tumor grading, should be carefully considered.
The radiological characteristics, tertiary lymphoid structures, and survival status associated with EGFR mutation in patients with subsolid nodules like stage I-II LUAD.
Authors: Xie Mei , Gao Jie , Ma Xidong , Song Jialin , Wu Chongchong , Zhou Yangyu , Jiang Tianjiao , Liang Yiran , Yang Chen , Bao Xinyu , Zhang Xin , Yao Jie , Jing Ying , Wu Jianlin , Wang Jianxin , Xue Xinying
Published: March 2024

Background

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) recommended for the patients with subsolid nodule in early lung cancer stage is not routinely. The clinical value and impact in patients with EGFR mutation on survival outcomes is further needed to be elucidated to decide whether the application of EGFR-TKIs was appropriate in early lung adenocarcinoma (LUAD) stage appearing as subsolid nodules.

Materials and methods

The inclusion of patients exhibiting clinical staging of IA-IIB subsolid nodules. Clinical information, computed tomography (CT) features before surgical resection and pathological characteristics including tertiary lymphoid structures of the tumors were recorded for further exploration of correlation with EGFR mutation and prognosis.

Results

Finally, 325 patients were enrolled into this study, with an average age of 56.8 ± 9.8 years. There are 173 patients (53.2%) harboring EGFR mutation. Logistic regression model analysis showed that female (OR = 1.944, p = 0.015), mix ground glass nodule (OR = 2.071, p = 0.003, bubble-like lucency (OR = 1.991, p = 0.003) were significant risk factors of EGFR mutations. Additionally, EGFR mutations were negatively correlated with TLS presence and density. Prognosis analysis showed that the presence of TLS was associated with better recurrence-free survival (RFS)(p = 0.03) while EGFR mutations were associated with worse RFS(p = 0.01). The RFS in patients with TLS was considerably excel those without TLS within EGFR wild type group(p = 0.018). Multivariate analyses confirmed that EGFR mutation was an independent prognostic predictor for RFS (HR = 3.205, p = 0.037).

Conclusions

In early-phase LUADs, subsolid nodules with EGFR mutation had specific clinical and radiological signatures. EGFR mutation was associated with worse survival outcomes and negatively correlated with TLS, which might weaken the positive impact of TLS on prognosis. Highly attention should be paid to the use of EGFR-TKI for further treatment as agents in early LUAD patients who carrying EGFR mutation.
Single-cell transcriptional signature-based drug repurposing and in vitro evaluation in colorectal cancer
Authors: Mahdi-Esferizi Roohallah , Shiasi Zahra , Heidari Razieh , Najafi Ali , Mahmoudi Issa , Elahian Fatemeh , Tahmasebian Shahram
Published: March 2024

Background

The need for intelligent and effective treatment of diseases and the increase in drug design costs have raised drug repurposing as one of the effective strategies in biomedicine. There are various computational methods for drug repurposing, one of which is using transcription signatures, especially single-cell RNA sequencing (scRNA-seq) data, which show us a clear and comprehensive view of the inside of the cell to compare the state of disease and health.

Methods

In this study, we used 91,103 scRNA-seq samples from 29 patients with colorectal cancer (GSE144735 and GSE132465). First, differential gene expression (DGE) analysis was done using the ASAP website. Then we reached a list of drugs that can reverse the gene signature pattern from cancer to normal using the iLINCS website. Further, by searching various databases and articles, we found 12 drugs that have FDA approval, and so far, no one has reported them as a drug in the treatment of any cancer. Then, to evaluate the cytotoxicity and performance of these drugs, the MTT assay and real-time PCR were performed on two colorectal cancer cell lines (HT29 and HCT116).

Results

According to our approach, 12 drugs were suggested for the treatment of colorectal cancer. Four drugs were selected for biological evaluation. The results of the cytotoxicity analysis of these drugs are as follows: tezacaftor (IC10 = 19 µM for HCT-116 and IC10 = 2 µM for HT-29), fenticonazole (IC10 = 17 µM for HCT-116 and IC10 = 7 µM for HT-29), bempedoic acid (IC10 = 78 µM for HCT-116 and IC10 = 65 µM for HT-29), and famciclovir (IC10 = 422 µM for HCT-116 and IC10 = 959 µM for HT-29).

Conclusions

Cost, time, and effectiveness are the main challenges in finding new drugs for diseases. Computational approaches such as transcriptional signature-based drug repurposing methods open new horizons to solve these challenges. In this study, tezacaftor, fenticonazole, and bempedoic acid can be introduced as promising drug candidates for the treatment of colorectal cancer. These drugs were evaluated in silico and in vitro, but it is necessary to evaluate them in vivo.
Periodontitis and Sjogren’s syndrome: a bidirectional two-sample mendelian randomization study
Authors: Liu Yixuan , Liu Nuozhou , Sun Peiyan , Liu Yi , Hua Wei
Published: March 2024

Objectives

Observational studies indicated a controversial relationship between periodontitis (PD) and Sjogren’s syndrome (SS). To overcome restrictions in conventional observational studies, we conducted a two-sample Mendelian randomization (MR) analysis to assess the potential bidirectional relationship between PD and SS.

Methods

We utilized the largest available genome-wide association study (GWAS) of European ancestry on both PD (17,353 cases-28,210 controls) and SS (2495 cases-365,533 controls) for MR genetic instrument selection. The random-effect inverse-variance weighted (IVW) method complemented by Causal Analysis Using Summary Effect (CAUSE), weighted median, weighted mode, simple mode, MR-Egger regression, and MR-pleiotropy residual sum and outlier (MR-PRESSO) was used for MR analysis. Subsequent pleiotropy and heterogeneity tests were conducted.

Results

IVW analysis exhibited neither an effect of PD on SS (OR = 0.939, 95%CI = 0.525–1.677, P = 0.8304) nor that of SS on PD (OR = 1.007, 95%CI = 0.977–1.038, P = 0.6440). The other five complementary methods further recognized the null association with an effect size close to one. No significant pleiotropy was detected in the relationship between PD and SS (P > 0.05). Heterogeneity existed in the effect of PD on SS but not vice versa.

Conclusions

No genetic causality between PD and SS or vice versa was supported by our results under MR assumptions and limitations. The study results provided new insights into the relationship between periodontal status and sjogren’s syndrome, highlighting the need for a more prudent medical intervention.
MAPK-dependent control of mitotic progression in S. pombe
Authors: Iglesias-Romero Ana Belén , Soto Terersa , Flor-Parra Ignacio , Salas-Pino Silvia , Ruiz-Romero Gabriel , Gould Kathleen L. , Cansado José , Daga Rafael R.
Published: March 2024

Background

Mitogen-activated protein kinases (MAPKs) preserve cell homeostasis by transducing physicochemical fluctuations of the environment into multiple adaptive responses. These responses involve transcriptional rewiring and the regulation of cell cycle transitions, among others. However, how stress conditions impinge mitotic progression is largely unknown. The mitotic checkpoint is a surveillance mechanism that inhibits mitotic exit in situations of defective chromosome capture, thus preventing the generation of aneuploidies. In this study, we investigate the role of MAPK Pmk1 in the regulation of mitotic exit upon stress.

Results

We show that Schizosaccharomyces pombe cells lacking Pmk1, the MAP kinase effector of the cell integrity pathway (CIP), are hypersensitive to microtubule damage and defective in maintaining a metaphase arrest. Epistasis analysis suggests that Pmk1 is involved in maintaining spindle assembly checkpoint (SAC) signaling, and its deletion is additive to the lack of core SAC components such as Mad2 and Mad3. Strikingly, pmk1Δ cells show up to twofold increased levels of the anaphase-promoting complex (APC/C) activator Cdc20Slp1 during unperturbed growth. We demonstrate that Pmk1 physically interacts with Cdc20Slp1 N-terminus through a canonical MAPK docking site. Most important, the Cdc20Slp1 pool is rapidly degraded in stressed cells undergoing mitosis through a mechanism that requires MAPK activity, Mad3, and the proteasome, thus resulting in a delayed mitotic exit.

Conclusions

Our data reveal a novel function of MAPK in preventing mitotic exit and activation of cytokinesis in response to stress. The regulation of Cdc20Slp1 turnover by MAPK Pmk1 provides a key mechanism by which the timing of mitotic exit can be adjusted relative to environmental conditions.
Early smoking lead to worse prognosis of COPD patients: a real world study
Authors: Wu Jiankang , Meng Weiwei , Ma Yiming , Zhao Zhiqi , Xiong Ruoyan , Wang Jiayu , Zhao Rui , Zeng Huihui , Chen Yan
Published: March 2024

Background

Smoking remains a major risk factor for the development and progression of chronic obstructive pulmonary disease (COPD). Due to the adolescent smoking associated with worse health state, the age, at which an individual started smoking, might play a key role in shaping the trajectory of COPD development and the severity.

Methods

We conducted an observational study from September 2016 through January 2023 of eligible patients hospitalized with COPD. Patients who started smoking during the alveolar development stage (ADS, smoking initiation ≤ 24 years old) were defined as early smoking patients, and patients who started smoking after ADS (smoking initiation > 24 years old) were defined as late smoking patients. We collected demographic and clinical data characterizing the patients and documented their condition from hospital discharge to follow-up. The primary endpoints were short-term (within one year), 3-year, and long-term (beyond 3 years) all-cause mortality after discharge.

Results

Among 697 COPD patients, early smoking patients had a lower smoking cessation rate (P < 0.001) and a higher smoking index (P < 0.001) than late smoking patients. Although adjusted smoking index, early smoking patients still had poorer lung function (P = 0.023), thicker left ventricular diameters (P = 0.003), higher frequency of triple therapy use during stable stage (P = 0.049), and more acute exacerbations in the past year before enrollment (P < 0.05). Survival analysis showed that they had a higher risk of death after discharge within three years (P = 0.004) and beyond three years (P < 0.001). Furthermore, even in early smoking COPD patients who quit smoking after adjusting the smoking index had poorer lung function (P < 0.05) and thicker left ventricular diameters (P = 0.003), and survival analysis also showed that they had a higher long-term mortality rate (P = 0.010) and shorter survival time (P = 0.0128).

Conclusion

Early smoking COPD patients exhibited multiple adverse clinical outcomes, including heavy cigarette addiction, compromised pulmonary function, augmented left ventricular diameter, and elevated mortality risk. Additional, smoking cessation could not bring enough improvement of health state in early smoking COPD patients as late smoking COPD patients. Consequently, early intervention and specialized cessation approaches for younger smokers are of paramount importance in this context.
Coordinated activation of DNMT3a and TET2 in cancer stem cell-like cells initiates and sustains drug resistance in hepatocellular carcinoma
Authors: Cheng Tao , Zhou Changli , Bian Sicheng , Sobeck Kelsey , Liu Yahui
Published: March 2024

Background

Resistance to targeted therapies represents a significant hurdle to successfully treating hepatocellular carcinoma (HCC). While epigenetic abnormalities are critical determinants of HCC relapse and therapeutic resistance, the underlying mechanisms are poorly understood. We aimed to address whether and how dysregulated epigenetic regulators have regulatory and functional communications in establishing and maintaining drug resistance.

Methods

HCC-resistant cells were characterized by CCK-8, IncuCyte Live-Cell analysis, flow cytometry and wound-healing assays. Target expression was assessed by qPCR and Western blotting. Global and promoter DNA methylation was measured by dotblotting, methylated-DNA immunoprecipitation and enzymatic digestion. Protein interaction and promoter binding of DNMT3a-TET2 were investigated by co-immunoprecipitation, ChIP-qPCR. The regulatory and functional roles of DNMT3a and TET2 were studied by lentivirus infection and puromycin selection. The association of DNMT and TET expression with drug response and survival of HCC patients was assessed by public datasets, spearman correlation coefficients and online tools.

Results

We identified the coordination of DNMT3a and TET2 as an actionable mechanism of drug resistance in HCC. The faster growth and migration of resistant HCC cells were attributed to DNMT3a and TET2 upregulation followed by increased 5mC and 5hmC production. HCC patients with higher DNMT3a and TET2 had a shorter survival time with a less favorable response to sorafenib therapy than those with lower expression. Cancer stem cell-like cells (CSCs) displayed DNMT3a and TET2 overexpression, which were insensitive to sorafenib. Either genetic or pharmacological suppression of DNMT3a or/and TET2 impaired resistant cell growth and oncosphere formation, and restored sorafenib sensitivity. Mechanistically, DNMT3a did not establish a regulatory circuit with TET2, but formed a complex with TET2 and HDAC2. This complex bound the promoters of oncogenes (i.e., CDK1, CCNA2, RASEF), and upregulated them without involving promoter DNA methylation. In contrast, DNMT3a-TET2 crosstalk silences tumor suppressors (i.e., P15, SOCS2) through a corepressor complex with HDAC2 along with increased promoter DNA methylation.

Conclusions

We demonstrate that DNMT3a and TET2 act coordinately to regulate HCC cell fate in DNA methylation-dependent and -independent manners, representing strong predictors for drug resistance and poor prognosis, and thus are promising therapeutic targets for refractory HCC.
Integrated analysis of disulfidptosis-related immune genes signature to boost the efficacy of prognostic prediction in gastric cancer
Authors: Li Jie , Yu Tian , Sun Juan , Ma Mingwei , Zheng Zicheng , He Yixuan , Kang Weiming , Ye Xin
Published: March 2024

Background

Gastric cancer (GC) remains a malignant tumor with high morbidity and mortality, accounting for approximately 1,080,000 diagnosed cases and 770,000 deaths worldwide annually. Disulfidptosis, characterized by the stress-induced abnormal accumulation of disulfide, is a recently identified form of programmed cell death. Substantial studies have demonstrated the significant influence of immune clearance on tumor progression. Therefore, we aimed to explore the intrinsic correlations between disulfidptosis and immune-related genes (IRGs) in GC, as well as the potential value of disulfidptosis-related immune genes (DRIGs) as biomarkers.

Methods

This study incorporated the single-cell RNA sequencing (scRNA-seq) dataset GSE183904 and transcriptome RNA sequencing of GC from the TCGA database. Disulfidptosis-related genes (DRGs) and IRGs were derived from the representative literature on both cell disulfidptosis and immunity. The expression and distribution of DRGs were investigated at the single-cell level in different GC cell types. Pearson correlation analysis was used to identify the IRGs closely related to disulfidptosis. The prognostic signature of DRIGs was established using Cox and LASSO analyses. We then analyzed and evaluated the differences in long-term prognosis, Gene Set Enrichment Analysis (GSEA), immune infiltration, mutation profile, CD274 expression, and response to chemotherapeutic drugs between the two groups. A tissue array containing 63 paired GC specimens was used to verify the expression of 4 DRIGs and disulfidptosis regulator SLC7A11 through immunohistochemistry staining.

Results

The scRNA-seq analysis found that SLC7A11, SLC3A2, RPN1 and NCKAP1 were enriched in specific cell types and closely related to immune infiltration. Four DIRGs (GLA, HIF-1α, VPS35 and CDC37) were successfully identified to establish a signature to potently predict the survival time of GC patients. Patients with high risk scores generally experienced worse prognoses and exhibited greater resistant to classical chemotherapy drugs. Furthermore, the expression of GLA, HIF-1α, VPS35, CDC37 and SLC7A11 were elevated in GC tissues. A high expression of GLA, HIF-1α, VPS35 or CDC37 was associated with more advanced clinical stage of GC and increased SLC7A11 expression.

Conclusion

Current study first highlights the potential value of DRIGs as biomarkers in GC. We successfully constructed a robust model incorporating four DRIGs to accurately predict the survival time and clinicopathological characteristics of GC patients.
Mg-ZIF nanozyme regulates the switch between osteogenic and lipogenic differentiation in BMSCs via lipid metabolism
Authors: Li Jinying , Chen Yongshao , Zha Dingsheng , Wu Chunhui , Li Xiaofen , Yang Li , Cao Hui , Cai Shexing , Cai Yuebo
Published: March 2024

The accumulation of reactive oxygen species (ROS) within the bone marrow microenvironment leads to diminished osteogenic differentiation and heightened lipogenic differentiation of mesenchymal stem cells residing in the bone marrow, ultimately playing a role in the development of osteoporosis (OP). Mitigating ROS levels is a promising approach to counteracting OP. In this study, a nanozyme composed of magnesium-based zeolitic imidazolate frameworks (Mg-ZIF) was engineered to effectively scavenge ROS and alleviate OP. The results of this study indicate that Mg-ZIF exhibits significant potential in scavenging ROS and effectively promoting osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Additionally, Mg-ZIF was found to inhibit the differentiation of BMSCs into adipose cells. In vivo experiments further confirmed the ability of Mg-ZIF to mitigate OP by reducing ROS levels. Mechanistically, Mg-ZIF enhances the differentiation of BMSCs into osteoblasts by upregulating lipid metabolic pathways through ROS scavenging. The results indicate that Mg-ZIF has potential as an effective therapeutic approach for the treatment of osteoporosis.
Landet: an efficient physics-informed deep learning approach for automatic detection of anatomical landmarks and measurement of spinopelvic alignment
Authors: MohammadiNasrabadi AliAsghar , Moammer Gemah , Quateen Ahmed , Bhanot Kunal , McPhee John
Published: March 2024

Purpose:

An efficient physics-informed deep learning approach for extracting spinopelvic measures from X-ray images is introduced and its performance is evaluated against manual annotations.

Methods:

Two datasets, comprising a total of 1470 images, were collected to evaluate the model’s performance. We propose a novel method of detecting landmarks as objects, incorporating their relationships as constraints (LanDet). Using this approach, we trained our deep learning model to extract five spine and pelvis measures: Sacrum Slope (SS), Pelvic Tilt (PT), Pelvic Incidence (PI), Lumbar Lordosis (LL), and Sagittal Vertical Axis (SVA). The results were compared to manually labelled test dataset (GT) as well as measures annotated separately by three surgeons.

Results:

The LanDet model was evaluated on the two datasets separately and on an extended dataset combining both. The final accuracy for each measure is reported in terms of Mean Absolute Error (MAE), Standard Deviation (SD), and R Pearson correlation coefficient as follows: $$[SS^\circ : 3.7 (2.7), R = 0.89]$$

[
S

S
∘

:
3.7

(
2.7
)

,
R
=
0.89
]

, $$[PT^\circ : 1.3 (1.1), R = 0.98], [PI^\circ : 4.2 (3.1), R = 0.93], [LL^\circ : 5.1 (6.4), R=0.83], [SVA(mm): 2.1 (1.9), R = 0.96]$$

[
P

T
∘

:
1.3

(
1.1
)

,
R
=
0.98
]

,

[
P

I
∘

:
4.2

(
3.1
)

,
R
=
0.93
]

,

[
L

L
∘

:
5.1

(
6.4
)

,
R
=
0.83
]

,

[
S
V
A

(
m
m
)

:
2.1

(
1.9
)

,
R
=
0.96
]

. To assess model reliability and compare it against surgeons, the intraclass correlation coefficient (ICC) metric is used. The model demonstrated better consistency with surgeons with all values over 0.88 compared to what was previously reported in the literature.

Conclusion:

The LanDet model exhibits competitive performance compared to existing literature. The effectiveness of the physics-informed constraint method, utilized in our landmark detection as object algorithm, is highlighted. Furthermore, we addressed the limitations of heatmap-based methods for anatomical landmark detection and tackled issues related to mis-identifying of similar or adjacent landmarks instead of intended landmark using this novel approach.
Acceptance and utilization of web-based self-help for caregivers of children with externalizing disorders
Authors: Wähnke Laura , Plück Julia , Bodden Mikel , Ernst Angela , Klemp Marie-Theres , Mühlenmeister Judith , Döpfner Manfred
Published: March 2024

Background

Web-based self-help interventions for parents of children with ADHD and other externalizing disorders have been proven to be effective. In order to recommend individualized and optimized interventions, a better understanding of the acceptance and utilization of this innovative treatment approach is needed. Previous research has frequently employed subjective reports of utilization, but the validity of these studies may be limited.

Methods

Data from the German WASH study were used. Participants (n = 276) were randomly assigned to the intervention condition (a) web-based self-help or (b) web-based self-help with optional telephone-based support calls. Data collection took place at baseline (T1) and 12 weeks later (T2). Utilization data were tracked using a log file generated for each participant at T2. Prediction models were calculated using CART (Classification and Regression Trees), a method known mostly from the field of machine learning.

Results

Acceptance, of the intervention as defined in this paper was very high on objective (89.4% have taken up the intervention) and subjective measures (91.4% reported having used the intervention and 95.3% reported they would recommend the intervention to a friend). The average number of logins corresponded to recommendations. Predictors of acceptance and predictors of utilization were similar and included, e.g., child’s externalizing symptoms, parental psychopathology, and above all additional telephone-based support by counselors.

Conclusions

Through a detailed identification of acceptance and utilization, and the predictors thereof, we were able to gain a better understanding of the acceptance and utilization of web-assisted self-help for a parent management intervention in the treatment of children with ADHD and ODD. These findings can be used to recommend web-based interventions to particularly suitable families. It should be noted that some form of support is required for an intensive engagement with the content of the program.

Trial Registration

The protocol of the study (German Clinical Trials Register DRKS00013456 conducted on January 3rd, 2018) was approved by the Ethics Committee of the University Hospital, Cologne.
The ARIA trial protocol: a randomised controlled trial to assess the clinical, technical, and cost-effectiveness of a cloud-based, ARtificially Intelligent image fusion system in comparison to standard treatment to guide endovascular Aortic aneurysm repair
Authors: Budge James , Carrell Tom , Yaqub Medeah , Wafa Hatem , Waltham Matt , Pilecka Izabela , Kelly Joanna , Murphy Caroline , Palmer Stephen , Wang Yanzhong , Clough Rachel E
Published: March 2024

Background

Endovascular repair of aortic aneurysmal disease is established due to perceived advantages in patient survival, reduced postoperative complications, and shorter hospital lengths of stay. High spatial and contrast resolution 3D CT angiography images are used to plan the procedures and inform device selection and manufacture, but in standard care, the surgery is performed using image-guidance from 2D X-ray fluoroscopy with injection of nephrotoxic contrast material to visualise the blood vessels. This study aims to assess the benefit to patients, practitioners, and the health service of a novel image fusion medical device (Cydar EV), which allows this high-resolution 3D information to be available to operators at the time of surgery.

Methods

The trial is a multi-centre, open label, two-armed randomised controlled clinical trial of 340 patient, randomised 1:1 to either standard treatment in endovascular aneurysm repair or treatment using Cydar EV, a CE-marked medical device comprising of cloud computing, augmented intelligence, and computer vision. The primary outcome is procedural time, with secondary outcomes of procedural efficiency, technical effectiveness, patient outcomes, and cost-effectiveness. Patients with a clinical diagnosis of AAA or TAAA suitable for endovascular repair and able to provide written informed consent will be invited to participate.

Discussion

This trial is the first randomised controlled trial evaluating advanced image fusion technology in endovascular aortic surgery and is well placed to evaluate the effect of this technology on patient outcomes and cost to the NHS.

Trial registration

ISRCTN13832085. Dec. 3, 2021
Epigenetic scores of blood-based proteins as biomarkers of general cognitive function and brain health
Authors: Smith Hannah M. , Moodie Joanna E. , Monterrubio-Gómez Karla , Gadd Danni A. , Hillary Robert F. , Chybowska Aleksandra D. , McCartney Daniel L. , Campbell Archie , Redmond Paul , Page Danielle , Taylor Adele , Corley Janie , Harris Sarah E. , Valdés Hernández Maria , Muñoz Maniega Susana , Bastin Mark E. , Wardlaw Joanna M. , Deary Ian J. , Boardman James P. , Mullin Donncha S. , Russ Tom C. , Cox Simon R. , Marioni Riccardo E.
Published: March 2024

Background

Epigenetic Scores (EpiScores) for blood protein levels have been associated with disease outcomes and measures of brain health, highlighting their potential usefulness as clinical biomarkers. They are typically derived via penalised regression, whereby a linear weighted sum of DNA methylation (DNAm) levels at CpG sites are predictive of protein levels. Here, we examine 84 previously published protein EpiScores as possible biomarkers of cross-sectional and longitudinal measures of general cognitive function and brain health, and incident dementia across three independent cohorts.

Results

Using 84 protein EpiScores as candidate biomarkers, associations with general cognitive function (both cross-sectionally and longitudinally) were tested in three independent cohorts: Generation Scotland (GS), and the Lothian Birth Cohorts of 1921 and 1936 (LBC1921 and LBC1936, respectively). A meta-analysis of general cognitive functioning results in all three cohorts identified 18 EpiScore associations (absolute meta-analytic standardised estimates ranged from 0.03 to 0.14, median of 0.04, PFDR < 0.05). Several associations were also observed between EpiScores and global brain volumetric measures in the LBC1936. An EpiScore for the S100A9 protein (a known Alzheimer disease biomarker) was associated with general cognitive functioning (meta-analytic standardised beta: − 0.06, P = 1.3 × 10−9), and with time-to-dementia in GS (Hazard ratio 1.24, 95% confidence interval 1.08–1.44, P = 0.003), but not in LBC1936 (Hazard ratio 1.11, P = 0.32).

Conclusions

EpiScores might make a contribution to the risk profile of poor general cognitive function and global brain health, and risk of dementia, however these scores require replication in further studies.
Effectiveness of molecular fingerprints for exploring the chemical space of natural products
Authors: Boldini Davide , Ballabio Davide , Consonni Viviana , Todeschini Roberto , Grisoni Francesca , Sieber Stephan A.
Published: March 2024

Natural products are a diverse class of compounds with promising biological properties, such as high potency and excellent selectivity. However, they have different structural motifs than typical drug-like compounds,e.g., a wider range of molecular weight, multiple stereocenters and higher fraction ofsp3-hybridized carbons. This makes the encoding of natural products via molecular fingerprints difficult, thus restricting their use in cheminformatics studies. To tackle this issue, we explored over 30 years of research to systematically evaluate which molecular fingerprint provides the best performance on the natural product chemical space. We considered 20 molecular fingerprints from four different sources, which we then benchmarked on over 100,000 unique natural products from the COCONUT (COlleCtion of Open Natural prodUcTs) and CMNPD (Comprehensive Marine Natural Products Database) databases. Our analysis focused on the correlation between different fingerprints and their classification performance on 12 bioactivity prediction datasets. Our results show that different encodings can provide fundamentally different views of the natural product chemical space, leading to substantial differences in pairwise similarity and performance. While Extended Connectivity Fingerprints are the de-facto option to encoding drug-like compounds, other fingerprints resulted to match or outperform them for bioactivity prediction of natural products. These results highlight the need to evaluate multiple fingerprinting algorithms for optimal performance and suggest new areas of research. Finally, we provide an open-source Python package for computing all molecular fingerprints considered in the study, as well as data and scripts necessary to reproduce the results, athttps://github.com/dahvida/NP_Fingerprints.
Large-scale next generation sequencing based analysis of SLCO1B1 pharmacogenetics variants in the Saudi population
Authors: Goljan Ewa , Abouelhoda Mohammed , Tahir Asma , ElKalioby Mohamed , Meyer Brian , Monies Dorota
Published: March 2024

Background

SLCO1B1 plays an important role in mediating hepatic clearance of many different drugs including statins, angiotensin-converting enzyme inhibitors, chemotherapeutic agents and antibiotics. Several variants in SLCO1B1 have been shown to have a clinically significant impact, in relation to efficacy of these medications. This study provides a comprehensive overview of SLCO1B1 variation in Saudi individuals, one of the largest Arab populations in the Middle East.

Methods

The dataset of 11,889 (9,961 exomes and 1,928 pharmacogenetic gene panel) Saudi nationals, was used to determine the presence and frequencies of SLCO1B1 variants, as described by the Clinical Pharmacogenetic Implementation Consortium (CPIC).

Results

We identified 141 previously described SNPs, of which rs2306283 (50%) and rs4149056 (28%), were the most common. In addition, we observed six alleles [*15 (24.7%) followed by *20 (8.04%), *14 (5.86%), *5 (3.84%), *31 (0.21%) and *9 (0.03%)] predicted to be clinically actionable. Allele diplotype to phenotype conversion revealed 41 OATP1B1 diplotypes. We estimated the burden of rare, and novel predicted deleterious variants, resulting from 17 such alterations.

Conclusions

The data we present, from one of the largest Arab cohorts studied to date, provides the most comprehensive overview of SLCO1B1 variants, and the subsequent OATP1B1 activity of this ethnic group, which thus far remains relatively underrepresented in available international genomic databases. We believe that the presented data provides a basis for further clinical investigations and the application of personalized statin drug therapy guidance in Arabs.
Chronic hypoxia remodels the tumor microenvironment to support glioma stem cell growth
Authors: Nicholson J. G. , Cirigliano S. , Singhania R. , Haywood C. , Shahidi Dadras M. , Yoshimura M. , Vanderbilt D. , Liechty B. , Fine H. A.
Published: March 2024

Cerebral organoids co-cultured with patient derived glioma stem cells (GLICOs) are an experimentally tractable research tool useful for investigating the role of the human brain tumor microenvironment in glioblastoma. Here we describe long-term GLICOs, a novel model in which COs are grown from embryonic stem cell cultures containing low levels of GSCs and tumor development is monitored over extended durations (ltGLICOs). Single-cell profiling of ltGLICOs revealed an unexpectedly long latency period prior to GSC expansion, and that normal organoid development was unimpaired by the presence of low numbers of GSCs. However, as organoids age they experience chronic hypoxia and oxidative stress which remodels the tumor microenvironment to promote GSC expansion. Receptor-ligand modelling identified astrocytes, which secreted various pro-tumorigenic ligands including FGF1, as the primary cell type for GSC crosstalk and single-cell multi-omic analysis revealed these astrocytes were under the control of ischemic regulatory networks. Functional validation confirmed hypoxia as a driver of pro-tumorigenic astrocytic ligand secretion and that GSC expansion was accelerated by pharmacological induction of oxidative stress. When controlled for genotype, the close association between glioma aggressiveness and patient age has very few proposed biological explanations. Our findings indicate that age-associated increases in cerebral vascular insufficiency and associated regional chronic cerebral hypoxia may contribute to this phenomenon.
Experimental study of sulfate crystallization damage to glutenite rock in the Maijishan Grottoes
Authors: Sheng Yumeng , Liu Ping , Shi Wentao , Sun Bo , Peng Ningbo , Jiao Dading , Li Changqing
Published: March 2024

Salt crystallization is one of the most important factors causing weathering in grottoes. Cumulative crystallization of salts causes damage such as flaking and peeling of the rocks and accelerates the weathering processes of the grottoes. The accumulated crystalline salts cause spalling, skinning and other damage and accelerate the weathering process of the grotto rock body. It is necessary to study the existing glutenite rock grottoes. This paper took the glutenite rock of the Maijishan Grottoes as a case study, and Na2SO4 or MgSO4 solutions were applied to glutenite rock specimens subjected to different deterioration cycles. The crystallization patterns of the two different salts and their damage to the glutenite rock were analyzed and studied, the mechanism for salt crystallization damage to the glutenite rock was explored, and the crystallization pressures of the two salts in the glutenite rock were derived with theoretical calculations. The results showed that both Na2SO4 and MgSO4 crystallization damaged the glutenite rock, and the former different sulfate solutions changed at different rates, and the changes in the wave caused faster damage than the latter. The physical indices of the rock samples in the velocities and tensile strengths were consistent. Na2SO4 was mainly accumulated on the surface of the specimen and damaged the glutenite rock centripetally via pulverization and exfoliation. MgSO4 mainly crystallized inside the glutenite rock, which created internal fissures and reduced the strength of the rock. The theoretical maximum crystallization pressures of Na2SO4 and MgSO4 in the glutenite rock specimens reached 33.00 MPa and 9.94 MPa, respectively. This study provides a theoretical basis for studies of salt crystallization in glutenite rock grottoes and provides a method for protecting the stones in cultural heritage sites against weathering.
Bilirubin metabolism: delving into the cellular and molecular mechanisms to predict complications
Authors: Kumbhar Sadhana , Musale Manish , Jamsa Anas
Published: March 2024

Bilirubin is a metabolic product of heme, and an increase in its level may be toxic to the body. It may be conjugated or unconjugated. Encephalopathy is caused by unconjugated bilirubin has the ability to pass through the blood-brain barrier, entering the central nervous system. Conjugated forms of bilirubin result in biliary obstruction and a change in urine colour due to a decrease in excretion. Excessive hemolysis can result from hereditary and autoimmune diseases, deficient RBC membranes, enzyme deficiency, and hemoglobin structural anomalies. In this review, we summarize all the possible mechanisms and complications regarding bilirubin. Cellular and molecular functions and mechanisms of bilirubin are explained, followed by several complications viz neurotoxicity, auditory dysfunction, and nephrotoxicity. The cause of bilirubin-induced neuronal cell damage is likely due to the elevated levels of unconjugated bilirubin in plasma, mitochondrial, and endoplasmic reticulum (ER) membranes. These disruptions in the membranes could lead to harmful effects such as neuronal excitotoxicity, energy failure in mitochondria, or an increased concentration of calcium within the cells. At the cellular level, bilirubin exerts its toxic effect by disturbing the normal functioning of neuronal cells. Bilirubin's presence can cause certain inflammatory responses, resulting in the activation of proinflammatory cytokines. Additionally, research has demonstrated that bilirubin can negatively affect auditory abilities. It disrupts the integrity of auditory pathways, resulting in auditory dysfunction and potentially causing long-term hearing impairments in infants affected by it. In conclusion, a comprehensive understanding of the complications associated with unconjugated bilirubin in neonates is essential for improving clinical management and outcomes. Understanding the cellular and molecular pathophysiology of high bilirubin may lead to a new therapeutic approach.
Infrastructure in Black
Authors: Kazanjian David
Published: March 2024

This essay interprets a 1714 petition by five Black Bostonians as a challenge to the role infrastructure played in racial capitalism's development in colonial New England. It theorizes this petition as an “ante-commons,” or a collective action at once before, alongside, and apposite to colonial modes of possession. It further shows how commons in early America did not simply oppose racial capitalism; they often supplemented enclosure, dispossession, and accumulation. Infra this whole story—underneath the extant archives and subsequent settler narratives of colonial New England's racial infrastructure—are intimately intertwined Black and Native lives and lands that unsettled possession in both its individuated and common forms.
Playing with Power: American Businesspeople, Diplomacy, and Electricity in Late Nineteenth- and Early Twentieth-Century Korea
Authors: Kahm Howard , Kim Hanmee Na
Published: March 2024

Henry Collbran and Harry Bostwick were the most successful American businessmen in Korea in the late nineteenth and early twentieth centuries. While they are well known for constructing the Seoul-Inch’ŏn railroad, the Seoul waterworks, and the streetcar system, their backgrounds and how they carried out their activities have not been deeply examined. Foreign businesspeople like Collbran and Bostwick possessed the technology and capital that Korea needed for modernization, but they had to navigate the volatile dynamics of domestic politics and international relations in the era of multilateral imperialism (1882–1905). This article argues that as Korea transitioned away from traditional East Asian diplomatic relations to Western-style diplomacy, Collbran and Bostwick functioned as unconventional nonstate actors who positioned themselves as unofficial American representatives to advance their business interests. While Collbran and Bostwick leveraged their position to extract the greatest possible benefits from the Koreans through mechanisms like high-interest debt traps, Emperor Kojong and Korean officials simultaneously sought to tie the American businessmen to Korea through diplomacy traps tied to concessions. These dynamics were particularly clear in the early electrification of Korea and the establishment and dissolution of the Seoul Electric Company.