bluuebunny/crossref_metadata_2025 huggingface dataset:
The association of dietary fatty acids intake with overall and cause-specific mortality: a prospective cohort study from 1999–2018 cycles of the NHANES
Authors: Zhang Zhaoxiang , Ding Lei , Liang Yali , Yang Hu , Zhu Yu
Published: February 2025

Background

Existing studies have evaluated the association of dietary fatty acids with mortality. However, the findings remained contentious. Our aimed to investigate the association of total dietary fat and each type of fatty acids with overall and cause-specific mortality.

Methods

We conducted a population-based prospective cohort study derived from the U.S. NHANES from 1999 to 2018. Baseline dietary information was assessed utilizing two 24-h dietary recalls. The death status was followed up to December 31, 2019. Hazard ratio (HR) was calculated by Cox regression and competing risk model. The effects of isocaloric replacement saturated fatty acids (SFAs) with monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) were estimated using the leave-one-out method.

Results

A total of 49,884 U.S. adults were included. 7,347 deaths, including 2,288 and 1,652 deaths from cardio-cerebrovascular disease (CCVD) and cancer, arose during 494,277 person-years. The intake of SFAs was positively associated with an increased risk of overall mortality, with extreme-quintile HR of 1.10 (95% CI: 1.02–1.19, Ptrend = 0.013); whereas an inverse association of PUFAs intake with overall mortality was observed, with extreme-quintile HR of 0.87 (95% CI: 0.81–0.94, Ptrend = 0.001). Greater intake of PUFAs was associated with a lower risk of CCVD-and cancer-specific mortality at borderline statistical significance. The isocaloric substitutions of 5% energy from MUFAs and PUFAs for SFAs was associated with 13 and 12% lower risk of overall mortality.

Conclusion

Greater intake of SFAs was positively associated with mortality, while greater intake of PUFAs was negatively associated with mortality. Reducing SFA by increasing MUFAs and PUFAs was an attractive strategy to lower mortality.
Nutritional therapy for MRSA sepsis complicated with pulmonary embolism in children under limited energy and nutrient conditions: a case report
Authors: Kong Lin , Xia Li , Zhou Fang , Tan Tian , Gao Zhongmin , Zhou Bo , Jiang Yao , Liu Chengjun , Pi Dandan
Published: February 2025

The nutritional treatment of methicillin-resistant Staphylococcus aureus sepsis combined with pulmonary embolism presents considerable challenges due to the risks associated with tube placement, coagulation disorders, severe infections, digestive limitations, and fluid restrictions in pediatric patients. This report discusses the case of an approximately 13-year-old female patient admitted with symptoms of right lower limb pain, fever, and cough accompanied by shortness of breath. The patient was assessed to be at moderate risk of malnutrition. In the early stages of treatment, permissive low-calorie enteral nutrition was administered alongside clinical interventions such as anti-infection therapy, anticoagulation, and empyema drainage. In the later stages, supplementary parenteral nutrition therapy was introduced, with careful monitoring of fluids restrictions, infection control, and coagulation index improvements. The patient’s condition improved significantly, and the wounds on the right chest and back healed well. A retrospective review of the literature over the past decade was conducted using domestic and international databases, alongside an analysis of current guidelines for nutritional support in critically ill children.
HMOS 2’FL and 3FL prevent house dust mite induced proinflammatory cytokine release in vitro and decrease specific IgE production in a murine allergic asthma model
Authors: Zuurveld Marit , de Kleer Janna W. M. , Berends Alinda J. , Kooy Manou M. , Van Ark Ingrid , Leusink-Muis Thea , Kettelarij Nienke , Folkerts Gert , Garssen Johan , van’t Land Belinda , Willemsen Linette E. M.
Published: February 2025

Introduction

Allergic asthma is characterized by sensitization to airborne allergens like house dust mite (HDM). Human milk oligosaccharides (HMOS) are linked to improved immune maturation and potentially alleviate allergy development.

Methods

A human in vitro model for crosstalk between bronchial epithelial cells (BECs), monocyte-derived DCs (moDCs) and T cells, during HDM exposure, was established. The immunomodulatory effects of the HMOS 2′-fucosyllactose (2’FL) and 3-fucosyllactose (3FL) were investigated in this in vitro model and subsequently in a house dust mite-induced allergic asthma murine model.

Results

HDM exposure during BEC-DC coculture enhanced type 2 instructing TSLP, while reducing regulatory TGFβ secretion. Coculture of HDM-primed DCs with T cells enhanced IL4 secretion. 2’FL or 3FL preincubation prevented HDM-induced TSLP and IL8 release from BEC-DC. HDM-allergic mice receiving a 1% 2’FL or 0,5% 3FL supplemented diet both had lower serum levels of HDM-specific IgE compared to mice fed control diet. In conclusion, a human in vitro coculture model for HDM-induced BEC-DC activation and subsequent type 2 T cell response was established. 2’FL or 3FL preincubation of BEC-DC prevented HDM-induced activation and modified downstream T cell responses in vitro. Both HMOS reduced HDM-specific IgE in a murine model for HDM allergic asthma, but did not protect against airway inflammation.

Conclusion

Here, we describe an in vitro human airway mucosal HDM sensitization model as relevant tool to reduce use of animals in studies aiming to prevent HDM allergic asthma. Both in vitro as well as in vivo, HMOS were found to drive away from a type 2 immune signature, paving the way to further investigate the potential allergy preventive effects of fucosylated HMOS.
Training modalities for elder sarcopenic obesity: a systematic review and network meta-analysis
Authors: Qiu Hao , Zheng Wanxia , Zhou Xi , Liu Qianrong , Zhao Xuehong
Published: February 2025

Introduction

Sarcopenic obesity (SO) is a condition characterized by the coexistence of age-related obesity and sarcopenia. This systematic review and network meta-analysis (NMA) aimed to compare the effects of different training modalities, such as aerobic training (AT), resistance training (RT), combined resistance with AT (CT), and multicomponent training (MCT) on body composition, muscle strength, and physical performance in elderly patients with SO.

Methods

We electronically searched randomized controlled trials, published from inception to March 2024 in PubMed, Embase, Cochrane Library, Web of Science and Scopus. Effect estimates were presented as mean differences (MD) or Standard Mean Difference (SMD) with 95% confidence interval (CI). The comprehensive effects of all treatments were ranked by the surface under the cumulative ranking (SUCRA) probabilities.

Results

14 trials enrolling 955 participants were included. The body fat percentage (BFP) in MCT (MD= −6.37, 95% CI: −8.67, −4.07), CT (MD = −2.08, 95% CI: −4.00, −0.16), and RT (MD = −1.85, 95% CI: −3.25, −0.44) was significantly lower than in the normal control group, with MCT showing superior effects compared to CT and RT. Furthermore, only MCT significantly improved fat-free mass (FFM; MD = 5.21, 95% CI:1.51, 8.91), as well as in body mass index (BMI; MD = 0.74, 95% CI:0.08, 1.40). In addition, handgrip strength (HGS) significantly improved under both MCT (SMD = 0.87, 95% CI: 0.19, 1.5) and RT(SMD = 0.84, 95% CI: 0.43, 1.25). The performance on the 30s chair stand test also yielded better outcomes for MCT (MD = 3.10, 95% CI: 1.33, 4 0.86), CT(MD = 2 0.50, 95% CI: 0.18, 5.18), and RT(MD = 3.91, 95% CI: 2.30, 5.52) when compared to the control group. Lastly, gait speed was enhanced by both MCT (MD = 0.35, 95% CI: 0.30, 0.41) and CT(MD = 0.14, 95% CI: 0.06, 0.21). The ranking results indicated that MCT was superior to other training modalities in enhancing body composition and gait speed. In contrast, RT appears to be more advantageous in the 30-second chair standing test and in improving HGS.

Conclusion

MCT outperformed other training modalities in improving body composition and gait speed. RT was more beneficial for the 30-second chair standing test and enhancing HGS. These findings provide valuable insights for clinicians and researchers to customize exercise prescriptions for older patients with SO.

Systematic review registration

http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42024544962.
Clinical effects of Bifidobacterium Longum Subsp. Infantis YLGB-1496 on children with respiratory symptoms
Authors: Li Pin , Mageswary Uma , Ali Adli , Taib Fahisham , Koo Thai Hau , Yusof Azianey , Jiang Hua , Lan Hanglian , Hung Weilian , Liong Min-Tze , Zhang Yumei
Published: February 2025

Objectives

This study aimed to examine the effects of Bifidobacterium longum subsp. infantis YLGB-1496 (B. infantis YLGB-1496) on the frequency of respiratory illness symptoms and immunity profiles among toddlers.

Methods

In this double-blind, randomized, placebo-controlled, 12-week intervention study, toddlers with at least 2 respiratory illness symptoms were randomly assigned into the probiotic (YLGB-1496) or placebo group at a 1:1 ratio. Follow-up examinations were conducted at baseline (week 0) and at weeks 6 and 12 of the intervention. The frequency of respiratory illness symptoms was assessed at these time points using validated questionnaires. Oral swabs and fecal samples were collected from participants at weeks 0, 6, and 12 to examine inflammatory cytokines.

Results

Among the 120 toddlers initially included in the study, 115 completed the 12-week intervention (58 in the YLGB-1496 group and 57 in the placebo group). The risk of antibiotic use or clinical visits was significantly lower in the YLGB-1496 group than in the placebo group (antibiotic use odds ratio (OR) = 0.37 [0.369, 0.372]; clinical visit, OR = 0.743 [0.741, 0.744]), but these differences were nonsignificant after adjusting for other potential confounders (p > 0.05). The YLGB-1496 group presented a lower incidence of several respiratory symptoms than the placebo group, including fever (p < 0.001), cough (p < 0.001), sneezing (p = 0.012), nose block (p = 0.001), and runny nose (p < 0.001). The results also revealed that the salivary cortisol concentration was significantly lower in the YLGB-1496 group than in the placebo group (p = 0.026), but no effects on INF-γ, IL-1β, IL-13, IL-4, or IL-10 were detected.

Conclusion

Bifidobacterium infantis YLGB-1496 may serve as a potential natural, nonpharmacological strategy for the safe management of respiratory tract issues in toddlers.

Clinical trial registration

The trial was registered at ClinicalTrials.gov (identifier number NCT05794815).
A retrospective study of neoadjuvant novel hormonal therapy prior to radical prostatectomy for high-risk prostate cancer
Authors: Shuai Hui , Zhang Wei , Liu Jianping , Zhang Peng , Chang Congwang , Fu Guanghua , Wu Tao
Published: February 2025

Purpose

This study aims to retrospectively describe the perioperative outcomes and short-term oncological outcomes of high-risk prostate cancer patients treated with neoadjuvant novel hormonal therapy (NNHT) combined with radical prostatectomy (RP) or RP alone.

Materials and Methods

Fifty-five male patients underwent RP and were categorized based on whether NNHT was administered preoperatively. Clinical baseline characteristics, perioperative outcomes, and biochemical recurrence (BCR) rate were summarized using mean, standard deviation, medians, interquartile ranges, and frequencies. Group 1 (n=20) received NNHT in combination with RP, while Group 2 (n=35) received RP alone. Patients in the NNHT group received androgen deprivation therapy (ADT) combined with either abiraterone (1,000 mg/d), enzalutamide (160 mg/d), or apalutamide (240 mg/d) before RP. SPSS Statistics 27 was used for statistical analysis.

Results

Among the 55 patients included in the study, the age, clinical T stage, N stage, biopsy Gleason scores, and the number of biopsy-positive needles appeared comparable across the two groups. However, patients in the NNHT+RP group had higher median preoperative serum prostate-specific antigen (PSA) levels (39.3 ng/mL, interquartile range [IQR]: 13.9-92.3) compared to the RP-only group (15.6 ng/mL, IQR: 10.7-19.8). The NNHT+RP group showed a lower proportion of positive surgical margins (PSM) (20%) compared to the RP-only group (49%). Similarly, the proportion of patients experiencing biochemical recurrence (BCR) within the follow-up period appeared lower in the NNHT+RP group (30%) compared to the RP-only group (57%). Additionally, operative time, hemoglobin decrease, transfusion rate, catheterization time, pathological T stage, and overall complication rates showed similar distributions across the two groups.

Conclusion

This study suggests that NNHT+RP may be associated with lower rates of PSM and BCR compared to RP alone. However, further studies with larger cohorts and longer follow-up are needed to assess its long-term impact on survival and other outcomes.
Pilot study of an arterial enhancement fraction-based model for progression prediction in HCC undergoing chemoembolization
Authors: Chai Bin , Xiang Dongqiao , Zhou Guofeng , Zheng Chuansheng
Published: February 2025

Objective

To develop a prognostic model including arterial enhancement fraction of residual tumor (AEF-RT) for predicting progression-free survival (PFS) in hepatocellular carcinoma (HCC) patients after drug-eluting beads transarterial chemoembolization (DEB-TACE).

Materials and methods

Between March 2019 and March 2024, 111 HCC patients undergoing DEB-TACE were randomly allocated to a training cohort and a validation cohort in a 7:3 ratio. LASSO regression was applied in the training cohort to identify risk factors for recurrence, which were subsequently used to construct the Cox model. Model performance was assessed using the concordance index (C-index, where 0.5 indicates non-informative discrimination and 1 represents perfect discrimination) and Brier score (ranging from 0 to 1, 0 indicating higher calibration) and was compared with five existing prognostic models.

Results

The final model, termed ADMAN model, incorporated AEF-RT, Diameter, Margin appearance, Aspartate transaminase, and Neutrophil-to-lymphocyte ratio. High-risk patients defined by ADMAN had 4.69 times greater progression risk than low-risk ones in the training cohort (p < 0.001) and 3.52 times greater in the validation cohort (p = 0.005). The C-index of ADMAN (0.75) was significantly higher than that of other models in the training cohort (p < 0.05 for all) and remained significantly higher than three of them in the validation cohort [0.71 vs. 0.55 (p = 0.041), 0.54 (p = 0.033), 0.53 (p = 0.004)]. The ADMAN model showed a significantly lower Brier score than that of other models at 6 months and 12 months in the training cohort (p < 0.05 for all). In the validation cohort, the ADMAN model remained to have significantly lower Brier score than the four models (p < 0.05) at 6 months, while it had significantly lower score than one model at 12 months.

Conclusions

The AEF-based model may be a promising tool for progression risk stratification in HCC patients undergoing DEB-TACE. Further external validation in independent cohorts with larger sample sizes is necessary to confirm the robustness of the ADMAN model.
Predicting microvascular invasion in solitary hepatocellular carcinoma: a multi-center study integrating clinical, MRI assessments, and radiomics indicators
Authors: Jian Wang , Zhan Lin , Zhaowang Lin , Ling Yang , Min Yu , Rong Xie , Wanxing Lin , Yongfei Yang , Haibin Tu
Published: February 2025

Background

Microvascular invasion (MVI) is a key prognostic factor in solitary hepatocellular carcinoma (HCC), significantly affecting treatment decisions and outcomes. Early prediction of MVI is crucial for enhancing clinical decision-making.

Objectives

This study aimed to develop and evaluate four predictive models for MVI: one based on clinical indicators, one on MRI assessments, one using radiomics, and a combined model integrating all data across multiple medical centers.

Methods

The study included patients with solitary HCC from three centers (Mengchao Hepatobiliary Hospital, The Second Hospital of Nanping, and Datian County General Hospital). The dataset was divided into an internal training set, validation set, and two external validation sets. Predictive models were built using clinical indicators, MRI, radiomics, and a combination of these. Model performance was assessed through ROC curves, calibration curves, and decision curve analysis (DCA). Lasso regression identified significant features, and SHAP analysis interpreted the model predictions.

Results

A total of 319 patients were analyzed: 199 from the internal center, 67 from Nanping, and 53 from Datian. The combined model, which integrated clinical, MRI, and radiomics features, showed superior performance, with an AUC of 0.95(95%CI:0.92-0.98) in the internal training set, 0.92(95%CI:0.83-1.00) in the internal validation set, 0.96(95%CI:0.92-1.00) in Nanping, and 0.94(95%CI:0.88-0.99) in Datian. Calibration curves confirmed the model’s accuracy, and NRI/IDI analyses highlighted its advantage over individual models. Key predictive indicators included pseudocapsule, peritumoral enhancement, and wavelet-based MRI features.

Conclusion

This multi-center study demonstrates the effectiveness of combining clinical, MRI, and radiomics data in predicting MVI in solitary HCC, with robust results across different medical centers. These models have potential to improve patient management and treatment planning.
Virusplot: a web server for viral integration analysis and visualization
Authors: Hu Erqiang , An Jianhong , Gersten Adam J , Wu Nicole , Kawachi Nicole , Zhu Jing , Rosenblatt Gregory , Augustine Stelby , Smith Richard V. , Segall Jeffrey E , Ostrer Harry , Amelio Antonio L , Chung Christine H. , Prystowsky Michael B. , Ow Thomas J. , Deng Wenjun , Yin Shanye
Published: February 2025

The integration of viral DNA into the human genome is a critical event in the pathogenesis of various cancers. This process leads to genomic instability, disrupts cellular regulatory mechanisms, and activates oncogenes or inactivates tumor suppressor genes. Despite significant advancements in genome sequencing technologies, there remains a notable lack of computational tools, particularly web-based applications, specifically designed for viral integration analysis and visualization. To address this gap, we present virusPlot, a web server with the following functional modules: (i) automatic retrieval of virus genome sequences and their annotation; (ii) visualization of virus integration locations and read counts through a graphical representation that links viral and host genome integration sites, facilitating the interpretation of integration patterns; (iii) analysis of virus integration hotspots using Fisher’s exact test; and (iv) integration of various functions into an interactive web platform via shinyapp. VirusPlot efficiently processes and visualizes integration data from viruses and host genomes, providing researchers with an intuitive and user-friendly analytical tool that simplifies the complexity of virus integration analysis.
Combinatorial genetic manipulation of Cx50, PI3K and PTEN alters postnatal mouse lens growth and homeostasis
Authors: Sellitto Caterina , White Thomas W.
Published: February 2025

Introduction

Phosphoinositide 3-kinase (PI3K), Phosphatase and tensin homolog (PTEN) and connexin50 (Cx50) have individually been shown to play critical roles in the growth, development and maintenance of the lens and to functionally interact in vitro. To elucidate how gap junctional coupling mediated by Cx50 and intracellular signaling mediated by PI3K and PTEN synergistically interact to regulate lens homeostasis in vivo, we generated and characterized double knockout animal models lacking the p110α subunit of PI3K and Cx50, or PTEN and Cx50.

Methods

We interbred lens specific p110α and PTEN conditional knockout animals with Cx50 deficient mice to generate double knockouts. Animals and eyes were weighed, lenses were dissected, photographed, measured, fixed and sectioned for histological analysis. Lens epithelial cell proliferation was determined using 5-ethynyl-2’-deoxyuridine (EdU) labeling.

Results

Double knockout of p110α and Cx50 led to a significant reduction in lens and eye size, and a high rate of lens rupture. The individual cell proliferation defects of the Cx50 and p110α single knockout lenses both persisted in the double KO. Double deletion of Cx50 and PTEN produced severe lens defects, including cataract, aberrant cell migration, altered cell proliferation, vacuole formation and lens rupture.

Conclusion

The severe phenotypes in p110α/Cx50 and PTEN/Cx50 double deficient lenses suggest that PI3K, PTEN and Cx50 participate in both distinct and common regulatory pathways that are necessary to maintain normal lens growth and homeostasis.
Pleuropulmonary blastoma in a 3-year-old child with persistent fever: a case report
Authors: Yue Ruiqi , Ma Guixia , Mao Li , Ni Qian
Published: February 2025

Pleuropulmonary blastoma (PPB) is a rare and highly aggressive malignant mesenchymal tumor, representing the most common malignant lung tumor in children. It is often misdiagnosed or underdiagnosed due to its clinical presentation, which mimics acute respiratory infections. Additionally, imaging manifestations are frequently indistinguishable from congenital respiratory malformations or severe lung infections. The tumor has high rates of recurrence and metastasis and has a poor prognosis. Currently, the internationally recommended treatment for PPB is a combination of surgery, chemotherapy, and radiotherapy. This article discusses the diagnosis and treatment of a 3-year-old girl with PPB combined with severe pneumonia.
Case report: Pharmacokinetic interaction involving sirolimus and regorafenib in patients with post-transplant recurrent hepatocellular carcinoma
Authors: Zhu Kongcai , Xiong Fang , Bai Haihong , Liu Wei
Published: February 2025

Background

Sirolimus is primarily metabolized by CYP3A4 and transported by P-gp. Drug interactions that affect this pathway can alter its plasma exposures, resulting in untargeted sirolimus concentrations.

Case summary

In this case report, we investigate a pharmacokinetic drug-drug interaction between regorafenib and sirolimus, mediated by CYP3A4 and P-gp, in a 56-year-old Chinese male with recurrent hepatocellular carcinoma post-liver transplantation. In this case, the patient’s baseline sirolimus trough blood concentration was 5.0 ng/mL prior to initiating a new cycle of regorafenib (80 mg once daily). Following a 7-day administration period of regorafenib, a notable elevation in sirolimus trough blood concentration to 12.3 ng/mL was observed. Upon cessation of regorafenib therapy for one week, the sirolimus trough blood concentration reverted back to 5.2 ng/mL. Nevertheless, upon resumption of regorafenib (160 mg once daily) treatment for an additional 10 days, the sirolimus trough blood concentration experienced a recurrence of increase, reaching 11.0 ng/mL. Following the confirmation of tumor progression, the discontinuation of regorafenib was deemed necessary. Consequently, a subsequent medical evaluation of the patient’s sirolimus trough blood concentration, undertaken precisely one month after cessation of regorafenib therapy, revealed a concentration level of 2.8 ng/mL. Based on the Drug Interaction Probability Scale, this interaction was deemed probable.

Conclusion

Regorafenib exerts a regulatory influence on the blood concentrations of sirolimus by inhibiting the activity of CYP3A4 and P-gp, potentially altering its pharmacokinetic profile. Given the potential for both excessive and inadequate immunosuppression to adversely affect patients with recurrent hepatocellular carcinoma post-liver transplantation, clinicians must maintain a heightened awareness of this drug-drug interaction.
The neutrophil-to-C3 ratio: unveiling diagnostic efficacy for lupus nephritis and association with reduced retinal vascular density in systemic lupus erythematosus
Authors: Maitiyaer Maierhaba , Li Peiyi , Li Huangdong , Jiang Dingwen , Zhang Jingyu , Yang Chuwei , Yang Xiaobin , Chen Chengmei , Huang Wenhui , Liu Zhiping , Yu Shuilian
Published: February 2025

Background

Lupus nephritis (LN) frequently manifests as a significant complication in systemic lupus erythematosus (SLE) patients, with emerging research indicating a plausible correlation between subclinical retinal involvement and renal manifestations. This study aims to investigate the relationship between the neutrophil-to-C3 ratio (NC3R) and both LN as well as retinal microvasculature damage among SLE patients.

Methods

In this cross-sectional study, a cohort of 220 participants (78 LN and 142 non-LN) was recruited. We assessed clinical indicators and organ involvement and conducted correlation analyses between NC3R and markers of lupus activity. Additionally, we analyzed the diagnostic performance of NC3R in diagnosing LN and constructed ROC curves. Variables such as clinical and laboratory data were screened by univariate and least absolute shrinkage and selection operator (LASSO) logistic regression modeling. After 10-fold cross-validation, the predictive model was built by multivariate logistic regression. We further examined the influence of NC3R on retinal vasculature density based on its cutoff value and conducted correlation analyses accordingly.

Results

The LN group exhibited a significant increase in NC3R compared to the group without LN (5.9 vs. 4.5, p = 0.007). NC3R demonstrated positive correlations with 24-h proteinuria (R = 0.329, p < 0.001) and systemic lupus erythematosus disease activity index (SLEDAI) score (R = 0.268, p < 0.001). Multiple regression analysis revealed NC3R as an independent risk factor for LN (OR: 2.03, p = 0.025). NC3R was proven valuable in distinguishing LN patients (AUC: 0.613), with an optimal cutoff value of 6.40 (sensitivity: 48.1%, specificity: 72.0%). Our results indicated that the lower NC3R group (NC3R < 6.40) exhibited reduced vascular density, particularly within the macular region. Furthermore, we observed a positive correlation between NC3R levels and vascular density.

Conclusion

NC3R demonstrated promising potential as a reliable indicator for predicting both LN and retinal microvasculature involvement. Consequently, the pre-treatment evaluation of NC3R had the potential to assist clinicians in identifying potential organ involvement among SLE patients.
Pharmacokinetics and bioequivalence of two formulations of the S-1 (tegafur/gimeracil/oxonate) capsule in Chinese cancer patients under fasting and fed conditions: a multicenter, randomized, open-label, single-dose, double-cycle crossover study
Authors: Lu Junli , Lei Yuyan , Mo Yuanyuan , Wang Xiangping , Liu Wanying , Yan Yu , Yang Hongying , Li Canxia , Huang Lifeng , Shen Qiuxia , Wang Caihong , Chen Jingjie , Chen Lulu , Li Xiaohui
Published: February 2025

Objective

S-1, an oral multicomponent capsule containing tegafur, gimeracil, and potassium oxonate, has demonstrated efficacy in various tumor types. This study aimed to assess the pharmacokinetics, bioequivalence (BE), and safety of a newly developed generic S-1 capsule compared to the original brand-name formulation in Chinese cancer patients under fasting and fed conditions.

Methods

A multicenter, randomized, open-label, single-dose, double-cycle crossover study was conducted in Chinese cancer patients. The study involved 120 subjects, with 60 assigned to the fasting group and another 60 to the fed group. In each study cycle, subjects were randomly assigned toreceive either the reference or test S-1 capsule at a 7-day interval. Blood samples were collected for analysis within 48 h after ingestion. The plasma concentrations of tegafur, 5-fluorouracil, gimeracil, and potassium oxonate were determined by liquid chromatography–tandem mass spectrometry (LC-MS/MS). The main pharmacokinetic (PK) parameters were calculated using the non-compartmental approach. BE was assessed through geometric mean ratios (GMRs) between the two formulations and their respective 90% confidence intervals (CIs). The safety of the two formulations was also evaluated.

Results

The pharmacokinetics of the two formulations were similar under both fasting and fed conditions. The 90% CIs of the GMRs for the maximum observed serum concentration (Cmax), AUC0-t, and AUC0-∞ ratios were observed to lie within the BE acceptance range of 80%–125%. Both formulations of the S-1 capsule exhibited similar adverse events (AEs), primarily including decreased white blood cell count and hypertension. These AEs were generally mild and transient. The safety profiles of the two formulations were found to be good and comparable, with no serious adverse events (SAEs) reported.

Conclusion

The newly developed generic S-1 and reference formulations exhibit comparable PK in Chinese cancer patients in the fasting and fed state. The formulations of S-1 showed good tolerability and a similar safety profile.

Clinical Trial Registration

http://www.chinadrugtrials.org.cn/index.html, identifier CTR20171562.
Bridging regulation and practice: CJEU and Dutch case law on botanical health claims
Authors: Lenssen Karin G. M. , de Boer Alie
Published: February 2025

Introduction

Even though botanicals are increasingly popular ingredients for food supplements, health claims related to their putative bene ts remain unclearly regulated.

Methods

Through an analysis of EU and national case law from the Netherlands, including self-regulatory decision-making, we have studied the implications of case law on botanical health claims.

Results

Our analysis reveals that there are multiple issues related to claims on botanical-containing products: whether it should be classi ed as food or medicine; what statements should be understood as health claims; what type of evidence should underlie health claims and, more specically, botanical health claims; and how to deal with online commercial communication. The case law analysis highlights rst that a gray area will continue to exist when classifying products as foods or medicinal products, particularly when it comes to products that contain botanical ingredients. Most importantly, our study also reveals that claims—even when they are on hold, like botanical claims—need a certain scienti c foundation before they can be used on products. Finally, the courts believe that even though on-hold claims will continue to give a certain level of uncertainty for food business operators, this is not a legal but rather a regulatory issue.

Discussion

The findings from our case law analysis highlight that even though case law is useful in further interpretation of legislation, it does not provide any policy advancement. In the case of botanicals, a political decision regarding their substantiation is highly desired.
Uncovering potential targets for antibody-drug conjugates in the treatment of gynecologic malignancies
Authors: Jiang Yuying , Xu Yuance , He Junqi , Sui Lei , Li Tian , Xia Nannan , Yao Qin
Published: February 2025

Background

Antibody-drug conjugates (ADCs) play an important role in the targeted therapy of gynecological malignancies. The purpose of this study was to investigate the expression of targets in gynecologic malignancies in order to predict the selection of targets for the development of antibody-drug conjugates.

Methods

In this article, we identified existing ADCs and their targets through clinical trial databases and public genomic datasets, performed differential analysis of tumor antigen targets (TATs) expression between tumor and normal tissues, and evaluated the necessity of the targets for tumor cell lines.

Results

In gynecologic malignancies, we have identified several highly expressed TATs, some of which have been targeted by FDA-approved ADCs, such as TROP2 and Nectin-4, although these drugs have not been approved for the treatment of gynecologic cancers. At the same time, we also observed that some targets of ADCs that have not yet been approved by the FDA also show high expression levels in gynecologic malignancies tissues, such as MSLN, ERBB3, NaPi2b, etc. Furthermore, we identified TATs with high expression levels in various pathological subtypes of ovarian, endometrial, and cervical cancer. Notably, some TATs are crucial to the survival of tumor cells, such as CD71, TOP1, and TDGF1, which are essential for the survival of ovarian, endometrial, cervical, and other tumor cells.

Conclusion

We have innovatively predicted the potential targets of ADCs in treating gynecological malignancies and provided a new perspective on applying some FDA-approved ADCs in indications for gynecological cancers.
Dual inhibitor of MDM2 and NFAT1 for experimental therapy of breast cancer: in vitro and in vivo anticancer activities and newly discovered effects on cancer metabolic pathways
Authors: Wang Wei , Aguilar Marlene , Datta Sayantap , Alley Abigail , Tadesse Meheret , Wang Xinshi , Gao Xia , Zhang Ruiwen
Published: February 2025

Introduction

The oncogene MDM2 has garnered attention not only for its role in cancer as a negative regulator of the tumor suppressor p53 but also for its p53-independent oncogenic activities. MDM2 also involves metabolic reprogramming, such as serine metabolism, respiration, mitochondrial functions, the folate cycle, and redox balance. Traditional MDM2 inhibitors blocking the protein-protein binding between MDM2 and p53 have shown limited clinical success in various stages of clinical trials, most likely due to low efficacy, drug toxicity, and drug resistance, highlighting the need for a novel, p53-independent strategy to inhibit MDM2. The present study investigated the antitumor effects of MA242, a novel MDM2 and NFAT1 inhibitor, in breast cancer models.

Methods

The anticancer activity and underlying mechanisms of MA242 were evaluated in vitro using breast cancer cell lines with different p53 backgrounds and in vivo using orthotopic and patient-derived xenograft models.

Results

We demonstrated that MA242 significantly inhibited cell viability and induced apoptosis in breast cancer cells, regardless of p53 status. Metabolic analysis revealed that MA242 notably disrupted nicotinamide metabolism, modified nucleotide metabolism, and elevated cellular oxidative stress by disturbing the redox balance. Furthermore, in animal models, MA242 reduced MDM2 expression and effectively inhibited tumor growth dependent on MDM2 expression without causing host toxicity.

Discussion

These findings highlight the potential of MA242 as a modulator of cancer metabolism and support its further development as a therapeutic option for aggressive breast cancers.
Resilience measurement and dynamic evolution of China’s provincial financial infrastructure
Authors: Li Guijun , Xiong Zhongwei , Kou Chenhuan , Li Shanshan
Published: February 2025

Financial infrastructure provides a fundamental guarantee for the sound and efficient operation of financial markets. This paper constructs a provincial-level financial infrastructure resilience evaluation index system, measures the level of financial infrastructure resilience of 31 provinces in China from 2005 to 2020, reveals the dynamic evolution characteristics of financial infrastructure resilience in the spatial and temporal dimensions, and analyzes the barrier factors affecting the dynamic change of financial infrastructure resilience level. The results of the study show that: Provincial financial infrastructure resilience level overall upward trend, in which resilience of risk and control is in a stagnant growth state, resilience of recovery and stability, resilience of transformation and development is on the rise; The level of financial infrastructure resilience and the rate of change generally show a spatial distribution trend of “low west and high east, north-south concave,” with the “wooden barrel effect” evident in the eastern region; Provincial financial infrastructure resilience is in the medium-low coupling stage, affected by the spillover effect is prone to form a “club convergence” phenomenon; The industrial structure, shadow banking risk, real estate liability risk, and fintech level are the main barrier factors to the resilience of financial infrastructure, resilience of risk and control, resilience of recovery and stability and resilience of transformation and development’s barrier degree respectively show a rising, declining, stable trend of change. Therefore, the follow-up should promote the coordinated development of regional finance and form a regional financial development pattern with staggered development and distinctive features; prevent the risks of regional financial infrastructure; and enhance the resilience of risk and control and the resilience of transformation and development.
Simultaneous assessment of mitochondrial and vascular function using the Flow Mediated Skin Fluorescence technique
Authors: Marcinek Andrzej , Katarzynska Joanna , Gebicki Jerzy
Published: February 2025

Flow Mediated Skin Fluorescence (FMSF) is a new non-invasive diagnostic method for assessing vascular circulation and/or metabolic regulation. The method measures stimulation of the circulation in response to post-occlusive reactive hyperemia (PORH). It analyzes the dynamical changes in NADH fluorescence emitted from skin tissue, providing information on mitochondrial metabolic status and intracellular oxygen delivery through the circulatory system. Assessment of the vascular state using the FMSF technique is based on three parameters: flowmotion (FM) under normoxia conditions, hypoxia sensitivity (HS), and hyperemic response (HRmax). The functioning of mitochondria can be assessed by analyzing the ischemic response (IRmax), hypoxia sensitivity (HS), and the basal level of NADH fluorescence. There is a close relationship between the functioning of mitochondria and the vascular system. Despite these interactions, mitochondrial and vascular regulatory function can be monitored separately as well as simultaneously by the FMSF technique. Uniquely, this approach delivers information on both mitochondrial and vascular function based on a single measurement.
Transcriptome profiling and RNA-Seq SNP analysis of reniform nematode (Rotylenchulus reniformis) resistant cotton (Gossypium hirsutum) identifies activated defense pathways and candidate resistance genes
Authors: Wubben Martin J. , Khanal Sameer , Gaudin Amanda G. , Callahan Franklin E. , McCarty Jack C. , Jenkins Johnie N. , Nichols Robert L. , Chee Peng W.
Published: February 2025

The reniform nematode (Rotylenchulus reniformis Linford & Oliveira) is a serious pathogen of Upland cotton (Gossypium hirsutum L.) wherever it is grown throughout the United States. Upland cotton resistance to R. reniformis derived from the G. barbadense accession GB713 is largely controlled by the Renbarb2 locus on chromosome 21. Renbarb2 has proven useful as a tool to mitigate annual cotton yield losses due to R. reniformis infection; however, very little is known about the molecular aspects of Renbarb2-mediated resistance and the gene expression changes that occur in resistant plants during the course of R. reniformis infection. In this study, two nearly isogenic lines (NILs), with and without the Renbarb2 locus, were inoculated with R. reniformis and RNAs extracted and sequenced from infected and control roots at 5-, 9-, and 13-dai (days after inoculation). A total of 966 differentially expressed genes (DEGs) were identified in the resistant NIL while 133 DEGs were discovered from the susceptible NIL. In resistant plants, biological processes related to oxidation-reduction reactions and redox homeostasis were enriched at each timepoint with such genes being up-regulated at 5- and 9-dai but then being down-regulated at 13-dai. DEGs associated with cell wall reinforcement and defense responses were also up-regulated at early timepoints in resistant roots. In contrast, in susceptible roots, defense-related gene induction was only present at 5-dai and was comprised of far fewer genes than in the resistant line. ERF, WRKY, and NAC transcription factor DEGs were greatly enriched at 13-dai in resistant roots but were absent in the susceptible. Cluster analysis of resistant and susceptible DEGs revealed an ‘early’ and ‘late’ response in resistant roots that was not present in the susceptible NIL. SNP analysis of transcripts within the Renbarb2 QTL interval identified five genes having non-synonymous mutations shared by other Renbarb2 germplasm lines. The basal expression of a single candidate gene, Gohir.D11G302300, a CC-NBS-LRR homolog, was ~3.5-fold greater in resistant roots versus susceptible. These data help us to understand the Renbarb2-mediated resistance response and provides a short list of candidate resistance genes that potentially mediate that resistance.
Analysis of cultivated land degradation in southern China: diagnostics, drivers, and restoration solutions
Authors: Liao Yanqing , Yu Zhihong , Kuang Lihua , Jiang Yefeng , Yu Chenxi , Li Weifeng , Liu Ming , Guo Xi , Ye Yingcong
Published: February 2025

Introduction

Cultivated land quality degradation is a critical challenge to food security, requiring effective nature-based restoration strategies based on comprehensive assessments of land quality. However, existing methods are often costly, limited in scope, and fail to capture the multidimensional complexity of the degradation processes.

Methods

This study integrated vegetation indices, topographic data, and soil physical and chemical properties to construct a model for identifying cultivated land degradation. Remote sensing indices were calculated using Google Earth Engine, enabling large-scale spatial analysis. Machine learning, combined with SHapley Additive exPlanations (SHAP), was employed to explore the driving factors of degradation.

Results

The results indicate that 11.86% of cultivated land in Yugan County is degraded, primarily in the central plain and riparian zones, driven by both natural factors (precipitation, temperature) and anthropogenic factors (straw incorporation, fertilization management). Soil erosion was concentrated in southern hills and near rivers, fertility decline occurred in the central plain, and soil acidification was evenly distributed with generally low degradation levels.

Discussion

Based on these findings, vegetation-based restoration solutions, including deep-rooted crops, crop rotation and intercropping, and straw incorporation, are proposed to address different types of cultivated land quality degradation and support sustainable land management.
Validation of the Slovenian versions of Child and Youth Resilience Measure-12 and Brief Resilience Scale among youth
Authors: Smrke Urška , Rehberger Ana , Močnik Sara , Špes Tanja , Mlakar Izidor , Plohl Nejc
Published: February 2025

Introduction

Resilience is the ability to adapt positively in the face of adversity, trauma, or significant stress and is a vital component of maintaining mental health and well-being. It is particularly shaped in young adulthood by navigating unique stressors, such as changes in living arrangements, relationships, and education. However, much of the existing research focuses on children or older adults, leaving a gap in our knowledge regarding resilience in young adulthood. Moreover, the existing resilience scales are seldom validated outside of English-speaking contexts. With this paper, we turn attention to validating two resilience measures, Child and Youth Resilience Measure-12 (CYRM-12) and Brief Resilience Scale (BRS), in Slovenian language, using a sample of young adults.

Method

We administered a survey among 330 young individuals (18–24 years) from Slovenia. Next to the central questionnaires, we also measured resilience with another scale, along with coping strategies, anxiety, depression, and quality of life.

Results

For both resilience scales, one-factor structures fitted the data well and both scales demonstrated good internal consistency. CYRM-12 and BRS showed positive associations with another resilience scale and adaptive coping strategies, negative associations with anxiety, depression, and maladaptive coping strategies, and a unique contribution to predicting quality of life (with CYRM-12 demonstrating somewhat greater predictive value for quality of life than BRS), pointing to good convergent, discriminant, and incremental validity, respectively.

Discussion

The results of our study suggest that CYRM-12 and BRS are both sufficiently reliable and valid for use among Slovenian young adults, with slightly stronger evidence supporting the validity of CYRM-12 compared to BRS.
A randomized, sham-controlled clinical trial to evaluate the NET Device™ for reducing withdrawal symptom severity during opioid discontinuation
Authors: Greenwald Mark K. , Arfken Cynthia L. , Winston Joe R.
Published: February 2025

Background

Neuromodulation is a promising approach for opioid discontinuation, as not all patients with opioid use disorder (OUD) seek pharmacotherapy. The NET Device is a non-invasive, battery-powered, portable, device that provides bilateral, transcranial, transcutaneous, alternating current stimulation (tACS) for patients experiencing opioid withdrawal. This clinical trial prospectively evaluated whether NET Device utilization is effective for persons with OUD undergoing opioid discontinuation without medications for OUD (MOUD).

Methods

This randomized, sham-controlled trial was conducted at a single residential treatment center. Persons with OUD undergoing opioid discontinuation were assigned to active or sham device treatment. Clinical Opiate Withdrawal Scale (COWS) total scores were measured prior to and during device use. We tested whether active stimulation would produce a clinically meaningful (≥15%) decrease in COWS score from baseline to 1-hr post-stimulation, compared to sham.

Results

108 participants (55 sham, 53 active; 59.3% male, 89.8% white; 71.3% fentanyl-positive) form the intent-to-treat dataset. Mean ( ± 1 SD) COWS score in the active device group decreased from baseline (18.1 + 4.4) to 1-hr (7.0 + 4.1); this 61.3% decrease (d=2.14) exceeded the pre-specified 15% criterion. COWS scores decreased more for active (-11.1 ± 5.2) than sham (-8.8 ± 6.3), p<.05, d=-.41. A higher proportion of participants in active vs. sham showed ≥15% reduction in COWS (98.1% vs. 83.6%), p=.016. Device utilization was longer for active than sham, 43.9 + 46.2 vs. 30.0 + 39.2 hours, p=.008, and fewer participants requested MOUD (26% vs. 49%, p<0.02).

Conclusion

The NET Device is effective, safe and well-tolerated for reducing opioid withdrawal symptoms. This device received FDA market clearance in May 2024.

Clinical trial registration

ClinicalTrials.gov, identifier NCT04916600.