bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Effectiveness of Laparoscopic versus Open Colectomy in Colon Cancer Patients: A Study Protocol for Emulating a Target Trial Using Cancer Registry Data
Authors: Abera Semaw Ferede , Robers Gabriele , Kästner Anika , Stentzel Ulrike , Weitmann Kerstin , Hoffmann Wolfgang 
Published: October 2024

Abstract

Introduction: The objective of this study is to compare the 5-year overall survival of patients with stage I – III colon cancer surgically treated by laparoscopic colectomy versus open colectomy. Methods: Using Mecklenburg-Western Pomerania Cancer Registry data from 2008 to 2018, we will emulate a phase III, multicenter, open-label, two-parallel-arm hypothetical target trial in adult patients with stage I – III colon cancer who received laparoscopic or open colectomy as an elective treatment. An inverse probability-weighted parametric (Royston‒Parmar) survival model (IPWPSM) will be used to estimate the hazard ratio of laparoscopic versus open surgery after baseline factors are balanced between the two treatment arms. An inverse probability weighted Kaplan‒Meier curve will be used to compare five-year overall survival in both treatment arms. The hazard ratio will be complemented by absolute differences in the restricted mean survival time (at 1-year, 3-years, and 5-years) between laparoscopic and open surgical treatment. Various comparator and sensitivity analyses will be performed to check the robustness of the results that will be estimated by the IPWPSM main model. Treatment period- and stage-specific results will also be provided. Discussion: This study aims to causally model the effect of laparoscopic versus open colectomy on 5-year overall survival using a target trial emulation approach. As the cancer registry data do not cover BMI, comorbidity, and previous abdominal surgery for non-malignant indications, the potential for residual confounding arising from these factors is a limitation of this study. This will be approached in a quantitative bias analysis using the E-method. The results will substantiate existing evidence on the comparative effectiveness of laparoscopic versus open colectomy in patients with stage I – III colon cancer and may guide clinical decisions as to whether a laparoscopic approach is as safe as an open approach in terms of improving 5-year overall survival in these patient groups.
Seroprevalence of human toxoplasmosis in Sudan from 1990 to 2022: A systematic review and meta-analysis
Authors: Mohammed Abdullah 
Published: October 2024

Abstract

Human toxoplasmosis is a prevalent zoonotic infection with significant public health implications. Sudan has a high burden of toxoplasmosis, but the overall prevalence of the infection is unknown. This meta-analysis was conducted to estimate the pooled seroprevalence of human toxoplasmosis in Sudan and identify its risk factors. This meta-analysis study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It included all studies conducted in both English and Arabic before March 31, 2023, from different databases. The results were analyzed using STATA software version 16.0.
Fifty-six studies with 10,006 participants were included in the analysis. The pooled seroprevalence of human toxoplasmosis in Sudan was 36% (95% confidence interval (CI): 31%–41%). Males had a higher pooled seroprevalence than females (56% vs. 44%). Other risk factors for toxoplasmosis infection included hemodialysis, being of childbearing age, HIV infection, and occupational exposure to animals. People living in southern Sudan had the highest pooled seroprevalence of toxoplasmosis (47%).
The findings of this meta-analysis suggest that human toxoplasmosis is a highly endemic infection in Sudan, with a higher prevalence in the southern region. Males, hemodialysis patients, women of childbearing age, HIV patients, and workers occupationally exposed to animals are at an increased risk of infection.
Nossa Senhora da Conceição da Roça do Alferes: doação; construção e rivalidade (XVIII/XIX)
Authors: Souza Alan de Carvalho 
Published: October 2024

O presente artigo tem como objetivo esclarecer o motivo pelo qual Nossa Senhora da Conceição foi escolhida como protetora do povoado que seria fundada posteriormente, a vila de Paty do Alferes. Contudo, após a análise das principais referências sobre a ocupação da localidade, foi possível perceber que os dois primeiros sesmeiros nem sequer se encontravam assentados na região. Assim, após esclarecer tais aspectos, a escolha de N. S. da Conceição como padroeira e a chegada dos fundadores da vila, apresentamos fatos relacionados a disputa pela construção da igreja que só foi entregue aos moradores em 1844. Isto é, cento e cinco anos após a escrituração da doação realizada em 1739 em benefício da então capela.
Palavras-chave: Nossa Senhora da Conceição; Paty do Alferes; Disputas
Uptake of Mesenchymal Stem Cell-Derived Exosomes in Mouse Brain through Intranasal Delivery
Authors: Zhang Zihe , He Siqi , Jiang Weijie , Lu Jing , Liu Songbin , Xu Wenjun , Wang Zhi , Lu Fangfang , Xiao Qiguo , Zhang Jia 
Published: October 2024

Introduction:
Exosomes are nanoscale extracellular vesicles that widely participate in
intercellular communication. An increasing number of studies have reported on the neuroprotective
effects of stem cell-derived exosomes in brain diseases through various delivery methods. However,
only a few reports are available on the delivery and uptake of stem cell-derived exosomes in the
brains of mice of different ages.

Methods:
PKH-26-labelled mesenchymal stem cell-derived exosomes were collected, and their uptake
was investigated in the brains of mice aged 2 weeks, 2 months, and >6 months, 24 hours after
intranasal delivery.

Results:
No exosomes were distributed in the whole brains of 2-week-old mice after 24 hours of intranasal
delivery. However, a small number of exosomes were found in the olfactory bulb, cortex, and
hippocampus of 2-month-old mice, with no exosomes observed in the cerebellum. In contrast, a large
number of exosomes were ingested in all brain regions, including the olfactory bulb, cortex, hippocampus,
and cerebellum, of >6-month-old mice.

Conclusion:
Exosomes can enter the brains of adult mice through intranasal administration, but there
are differences in the uptake rate among mice of different ages. These findings provide a theoretical
basis for the future clinical administration of exosomes for treating brain disorders.
A Phase II Clinical Study on Apatinib Plus Vinorelbine in Refractory HER2-Negative Breast Cancer and its Metabolic Implications of Drug Resistance
Authors: Wu Jing , Deng Pan , Zou La , Liu Xiaoyu , Tang Xianjun , Zeng Xiaohua , Liu Shengchun 
Published: October 2024

Background:
Apatinib, a tyrosine-kinase inhibitor that targets the vascular endothelial growth factor receptor 2, contributes to the inhibition of angiogenesis. Vinorelbine, a semisyn-thetic vinca alkaloid, primarily inhibits metaphase mitosis of cancer cells through its interactions with tubulin. This study aimed to evaluate whether apatinib combined with vinorelbine was ef-fective and safe for refractory human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients who failed taxanes and/or anthracycline and analyze the possible mechanism of drug resistance through metabolomic analysis.

Methods:
Eligible patients were HER2-negative, inoperable, locally advanced, or metastatic breast cancer patients who progressed after at least one chemotherapy regimen in this present prospective phase II study. Patients took oral apatinib (250-500 mg/day) plus intravenous infusion of vinorelbine (25 mg/m2 on day 1, day 8 at 3-week intervals). Objective response rate (ORR) was our primary endpoint, while disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity were our secondary endpoints. The exploratory purpose was to identify biomarkers or drug resistance mechanisms through metabolomics changes before and after the combination therapy.

Results:
Between September, 2019 and June, 2022, a total of 34 patients were included. ORR and DCR were 32.4% (11/34) and 85.3% (29/34), respectively. The median PFS was 5.0 months (95% CI, 3.766-6.234), while the median OS was 13.0 months (95% CI, 8.714-17.286). Side effects included hematologic toxicity, gastrointestinal reaction, and sinus tachycardia, which were mild to moderate. The mainly disturbed metabolic pathways were the cAMP signaling pathway, the alanine/aspartate/glutamate metabolism, the central carbon metabolism in cancer, the beta-alanine metabolism, the butanoate metabolism, and the glyoxylate and dicarboxylate metabolism, which may lead to the resistance of patients to this combination therapy.

Conclusion:
Apatinib combined with vinorelbine is effective and safe in patients with locally advanced or metastatic refractory HER2-negative breast cancer. The findings of this study con-tribute to a better understanding of the metabolic effect of apatinib and vinorelbine therapy.
MMP7, Regulated by c-Jun, is Involved in Oral Squamous Cell Carcinoma and Associated with Cancer-Related Fibroblasts Infiltration
Authors: Wei Jian , Jiang Xiaoxi , Xu Yiwen , Nie Minhai , Yang Sen , Chen Xiao , Huang Lijuan , Liu Xuqian 
Published: October 2024

Objective:
This study aimed to analyze the expression of Matrix Metalloproteinase 7 (MMP7) and molecular mechanism at the Transcription Factor (TF) level in Oral Squamous Cell Carcinoma (OSCC).

Methods:
MMP7 expression was preliminarily explored in Head and Neck Squamous Cell Car-cinoma (HNSCC) in the online database, followed by functional analysis and prediction of TF of MMP7. IHC was employed to detect MMP7 levels in OSCC samples. SCC9 and 293T cells were used to explore the transcriptional and regulatory effects of predicted TF on MMP7 by reporter double luciferase assay, RT-qPCR, western blotting, and cellular immunofluorescence. Transwell and TUNEL were employed to detect the migration and apoptosis.

Results:
MMP7 was significantly up-regulated in HNSCC and OSCC tissues. Moreover, MMP7 was positively correlated with CAFs and significantly enriched in the signaling pathway of RNA degradation. The c-Jun pathway was also up-regulated in OSCC tissues, and predicted to be optimal TF of MMP7 with positive regulatory relationship. In OSCC, silencing and over-expression of c-Jun significantly decreased and increased the level of MMP7. Meanwhile, c-Jun affected the behavior of SCC9 cells, which showed that after c-Jun gene silencing, the ability of cell migration was weakened, while apoptosis was enhanced. When c-Jun gene was overexpressed, the migration ability was enhanced, but apoptosis was not significantly affected.

Conclusion:
MMP7 has been proven to be a key protein in the development of OSCC, and has the potential to become a biological marker and therapeutic target. It has been found that c-Jun could bind to the MMP7 promoter region, and the silencing or overexpression of c-Jun can positively regulate the expression of MMP7.
In silico Profiling and Pharmacokinetic Modelling of Olivetol: Evaluating its Potential as a Therapeutic Agent for Diabetic Wound Healing
Authors: Shanmugasundaram Nirenjen , Jayasankar Narayanan 
Published: October 2024

Background:
Diabetic wound healing poses a significant challenge due to the intricate
disruptions in cellular and molecular processes induced by hyperglycaemia, leading to delayed or
impaired tissue repair. Computational techniques offer a promising avenue for unravelling the complexities
of diabetic wound healing by elucidating the molecular mechanisms involved.

Methodology:
This study utilized in silico molecular docking and dynamics simulations to explore
the potential therapeutic effectiveness of olivetol, a phenolic compound, in the context of diabetic
wound healing. Furthermore, computational methodologies, encompassing pkCSM, Swiss ADME,
OSIRIS® property explorer, PASS online web resource, and MOLINSPIRATION® software, were
employed to forecast the pharmacokinetic properties, biological actions, and in vitro analyses, such
as MTT and scratch assays, to evaluate the therapeutic effectiveness of olivetol in wound healing.

Results and Discussion:
Our findings have revealed olivetol to be a promising candidate for targeting
multiple pathways implicated in diabetic wound healing. Its ability to modulate inflammation, oxidative
stress, extracellular matrix remodeling, angiogenesis, and cell signaling suggests a multifaceted
approach to promoting effective wound repair. Moreover, olivetol has been found to demonstrate
strong binding affinity with key MRSA target proteins, indicating its potential as an antimicrobial
agent against MRSA infections in diabetic wounds. The in vitro MTT assay demonstrated cell viability
with an IC50 value of 40.80 μM, highlighting its cytotoxicity potential. Additionally, the
scratch assay confirmed promising wound healing activity, showcasing its effectiveness in promoting
cell migration and closure.

Conclusion:
Olivetol emerges as a promising candidate for targeted interventions in non-healing diabetic
wounds, particularly due to its ability to address prolonged inflammation, a common obstacle
in diabetic wound healing.
A Theoretical Study on Derivatives of 1,2,4-Trioxane as Potential Anti-malarials and an Analysis of the Mechanism of Drug Release in the Presence Of Fe(III) Ions
Authors: Bayat Zakiyeh 
Published: October 2024

Introduction:
A mechanism has been proposed for the targeted transfer of an antimalarial
drug, which involves 1, 2, and 4 trioxane (TRX) reagents. The trioxane ring is sensitive to ferrous
iron, Fe(II), and when exposed to it, it breaks down into smaller pieces, releasing the antimalarial
drug mML (a mock form of DPA1 inhibitor ML4118S).

Method:
The oxane ring is attached to a nanoparticle called adamantane, which helps facilitate the
reaction. The mechanism has been investigated using two reactants: TRX-R-mML and TRX-H-mML
complexes (R is a side chain). The researcher used the transition state theory, the Hartree-Fock level
(HF), and the ground state series 6-31G** to investigate the mechanism. The physicochemical and
geometric properties of the components involved in the reaction were measured to explain the mechanism
better.

Results:
The results indicate that the R as a side chain significantly affects the mentioned mechanism
and properties. Additionally, the results of the calculations show the stability of the complexes required
as reactants in the reaction.

Conclusion:
The TRX-mML-R complex has more strength, and polarity than TRX-mML-H, and the
energy level of the transition state of TRX-mML-R is lower than that of TRX-mML-H, indicating
faster passage of raw materials.
Application of Machine Learning Methods in Predicting Lysine-specific
Histone Demethylase 1 (LSD1) Inhibitors
Authors: Kuang Zheng-Kun , Huang Qing , Huang Lixia 
Published: October 2024

Background:
Lysine-specific histone demethylase 1 (LSD1) is a well-known anti-cancer
target for drug discovery. Novel reversible inhibitors of LSD1 are desirable to be developed.

Objective:
This study aimed to build reliable predictive models to evaluate the antineoplastic efficacy
of compounds and reveal the structural foundation underlying the inhibitory activity of LSD1.

Methods:
Multiple artificial intelligence algorithms were utilized in the development of quantitative
structure-activity relationship (QSAR) models. A dataset comprising 915 compounds with welldefined
IC50 values against LSD1 was assembled for analysis. The structures of these compounds
were described by different descriptor packages. Principal component analysis (PCA) was performed
to explore the chemical space distribution of each dataset. Y-randomization test and applicability
domain (AD) analysis were deployed to validate the reliability of models.

Results:
For regression models, a consensus model was constructed by integrating the predictions of
four top-performing individual models (SVM_ECFP4, RFR_PyDescriptor, RFR_RDKIT, and
TRANSNNI), resulting in enhanced predictive performance as compared to the individual models.
The consensus model achieved a determination coefficient (r2, for the test set) value of 0.82. For
classification models, the consensus model was derived from the amalgamation of three individual
models (ASNN_RDKIT, ASNN_ECFP4, and RFR_ECFP4), and the overall prediction accuracy of
the model was 0.96 for external validation.

Conclusion:
The reliable models could be used to identify highly active LSD1 inhibitors for the
purpose of efficient virtual screening. In addition, the important molecular properties and structural
fragments derived from this work can provide guidance for the structural optimization of novel
LSD1 inhibitors.
Flemingia Strobilifera– An Updated Review on its Pharmacognostic and Pharmacological Properties
Authors: Sahu Asmit , Dubey Neha , Satapathy Trilochan , Pandey Ravindra Kumar , Shukla Shiv Shankar , Gidwani Bina 
Published: October 2024

Background:
Our health care system greatly benefits from the use of old medical techniques.
In Ayurvedic medicine to improve manhood, Flemingia strobilifera (Lam.) is utilized as
an herb. The Fabaceae family, which includes Flemingia strobilifera (Palas), is widely cultivated
throughout India. There are more than forty species of Flemingia throughout the globe; out of
which 15 species of this genus are in India.

Objective:
To learn more details about this plant and various species of Flemingia, specifically the
chemical makeup of the plant, its species, and/or its elements, traditional and medical uses for the
plant. This review article also focuses on the origin, history, classification, phytochemistry, morphology,
microscopy, and pharmacological aspects.

Methods:
A detailed and extensive literature survey through research findings, review articles,
Google sources, database etc was done to explore the aspect of Flemingia species for its various
physical, chemical, pharmacological, phytochemistry and related fields.

Results:
Our findings report that several representatives of this genus have been employed as vermifuges
and remedies for fever, diarrhea, indigestion in traditional medicine. The plant's anthelmintic,
anticancer, antirheumatic, antiinflammatory, antioxidant and antihistaminic effects are
well documented. According to literature reports, the chemical constituents of this genus' are
flavonoids, glycosides, chalcones, epoxy chromenes, and pterocarpans. Rural and ethnic people
regularly use this plant to treat a range of diseases.

Conclusion:
Research on Flemingia strobilifera has a bright future thanks to its strong natural origin.
The uniqueness and usefulness of Flemingia strobilifera was obscured. In future, many more
potential of Flemingia could be investigated in combination with other herbs.
MG132-mediated Suppression of the Ubiquitin-proteasome Pathway Enhances the Sensitivity of Endometrial Cancer Cells to Cisplatin
Authors: Zhang Zhanhu , Ding Yiqian 
Published: October 2024

Background:
Tumor cell resistance to cisplatin is a common challenge in endometrial cancer chemotherapy,
stemming from various mechanisms. Targeted therapies using proteasome inhibitors, such as MG132,
have been investigated to enhance cisplatin sensitivity, potentially offering a novel treatment approach.

Objective:
The aim of this study was to investigate the effects of MG132 on cisplatin sensitivity in the human
endometrial cancer (EC) cell line RL95-2, focusing on cell proliferation, apoptosis, and cell signaling.

Methods:
Human endometrial cancer RL95-2 cells were exposed to MG132, and cell viability was assessed in a
dose-dependent manner. The study evaluated the effect of MG132 on cisplatin-induced proliferation inhibition
and apoptosis, correlating with caspase-3 activation and reactive oxygen species (ROS) upregulation. Additionally,
we examined the inhibition of the ubiquitin-proteasome system and the expression of pro-inflammatory cytokines
IL-1β, IL-6, IL-8, and IL-13 during MG132 and cisplatin co-administration.

Results:
Human endometrial cancer RL95-2 cells were exposed to MG132, and cell viability was assessed in a
dose-dependent manner. The study evaluated the effect of MG132 on cisplatin-induced proliferation inhibition
and apoptosis, correlating with caspase-3 activation and reactive oxygen species (ROS) upregulation. Additionally,
we examined the inhibition of the ubiquitin-proteasome system and the expression of pro-inflammatory cytokines
IL-1β, IL-6, IL-8, and IL-13 during MG132 and cisplatin co-administration.

Result:
MG132 exposure significantly reduced cell viability in a dose-dependent manner. It augmented cisplatin-
induced proliferation inhibition and enhanced apoptosis, correlating with caspase-3 activation and ROS upregulation.
Molecular analysis revealed a profound inhibition of the ubiquitin-proteasome system. MG132 also
significantly increased the expression of cisplatin-induced pro-inflammatory cytokines, suggesting a transition
from chronic to acute inflammation.

Conclusion:
MG132 enhances the therapeutic efficacy of cisplatin in human EC cells by suppressing the ubiquitin-
proteasome pathway, reducing cell viability, enhancing apoptosis, and shifting the inflammatory response.
These findings highlighted the potential of MG132 as an adjuvant in endometrial cancer chemotherapy. Further
research is needed to explore detailed mechanisms and clinical applications of this combination therapy.
Formulation Optimization and Evaluation of Patented Solid Lipid Nanoparticles of Ambrisentan for Pulmonary Arterial Hypertension
Authors: Shewale Harshada , Kanugo Abhishek 
Published: October 2024

Background:
Ambrisentan is a new endothelin receptor antagonist extensively used to
manage pulmonary or pulmonary arterial hypertension.

Objective:
The therapeutic efficacy of Ambrisentan is limited due to its reduced solubility, higher
log P (3.4), and thus less bioavailability. The recent investigation was concentrated on the improvement
of solubility, and bioavailability of Ambrisentan for the therapy of hypertension via solid lipid
nanoparticles (SLN) administered orally.

Methods:
XRD evaluated the compatibility of Ambrisentan with lipids with FTIR, DSC, and crystalline
nature. The SLN was developed by High-pressure homogenization method. The Glyceryl
monostearate and Tween 80 indicated the highest solubility, hence selected. The optimization was
performed with Box-Behnken Design considering the concentration of GMS (X1), Tween 80 (X2),
stirring speed (X3) as independent factors and particle size (Y1), entrapment efficiency (Y2) as dependent
factors. The Patents on the SLN are Indian 202321053691, U.S. Patent, 10,973,798B2, U.S.
Patent 10,251,960B2, U.S. Patent 2021/0069121A1 and U.S. Patent 2022/0151945A1.

Results:
The optimized batch F1 showed particle size (130 nm), ZP (-18.9 mV), and entrapment efficiency
(85.73 %). The dual release pattern (prompt and sustained) was achieved with the SLNloaded
Ambrisentan for about 24 hours. The lyophilized sample was subjected to SEM, which also
revealed a spherical shape of a colloidal dispersion with a particle size of 126 nm. Hence, the F1
batch is highly recommended for solid oral delivery and also for the pilot-plant scale-up.

Conclusion:
A marked improvement in the solubility and dissolution of Ambrisentan was attained
with the SLN. Moreover, the sustained delivery via the oral route enabled the patient's comfort,
compliance, and therapeutic efficacy.