bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct Bilirubin, but not Indirect Bilirubin, is Associated with Short-term
Adverse Events in HFpEF
Authors: Wang Sunying , Chen Yan , Ma Hanghao , Wang Yuwei , Luo Manqing , Xie Xianwei , Yang Qingyong , Lin Kaijin , Lin Meihua , Lin Lin , Chen Ping , Zheng Qiaowen , Sun Fuqing 
Published: February 2024

Objective:
Abnormal live function tests have been identified as independent risk factors
for ominous prognosis in patients with heart failure. However, most of the previous studies have
failed to determine the contribution of direct bilirubin (DBIL) and indirect bilirubin (IBIL) separately.
Hence, we aimed to explore whether DBIL or IBIL is correlated with the prognosis of heart failure
with preserved ejection fraction (HFpEF).

Methods:
A total of 19837 patients were hospitalized for HFpEF between January 2012 and January
2022 in Fuqing City Hospital affiliated with Fujian Medical University. The primary endpoint
was in-hospital all-cause mortality. Secondary endpoints included in-hospital cardiovascular mortality
and 30-day re-admission for heart failure.

Results:
Univariable analysis indicated that patients with elevated DBIL or IBIL were exposed to a
higher risk of mortality and re-admission. However, in multivariable models, both ln-transformed
DBIL and TBIL, but not IBIL, were independent risk factors for in-hospital all-cause mortality
[hazard ratio (HR)=1.796, 95% confidential interval (CI)=1.477-2.183, P＜0.001; HR=1.854, 95%
CI=1.461-2.352, P＜0.001; HR=1.161, 95% CI=0.959-1.407, P=0.126] and in-hospital cardiovascular
mortality (HR=1.831, 95% CI=1.345-2.492, P＜0.001; HR=1.899, 95% CI=1.300-2.773,
P=0.001; HR=1.145, 95% CI=0.841-1.561, P=0.389). Only DBIL remained independently associated
with 30-day readmission for heart failure (HR=1.361, 95% CI=1.036-1.787, P=0.027). Adding
ln-transformed DBIL to model 1 increased its discriminatory capacity (C-statistic: 0.851 to 0.869,
respectively), whereas adding ln-transformed IBIL yielded little increment (C-statistic: 0.851 to
0.852, respectively).

Conclusion:
DBIL, but not IBIL, was associated with short-term ominous prognosis in patients
with HFpEF. Hence, DBIL may be the superior predictor for prognosis in HFpEF.
CRISPR-Based Therapies: Revolutionizing Drug Development and
Precision Medicine
Authors: Chanchal Dilip Kumar , Chaudhary Jitendra Singh , Kumar Pushpendra , Agnihotri Neha , Porwal Prateek 
Published: February 2024

Abstract:
With the discovery of CRISPR-Cas9, drug development and precision medicine have
undergone a major change. This review article looks at the new ways that CRISPR-based therapies
are being used and how they are changing the way medicine is done. CRISPR technology's
ability to precisely and flexibly edit genes has opened up new ways to find, validate, and develop
drug targets. Also, it has made way for personalized gene therapies, precise gene editing, and advanced
screening techniques, all of which hold great promise for treating a wide range of diseases.
In this article, we look at the latest research and clinical trials that show how CRISPR could be
used to treat genetic diseases, cancer, infectious diseases, and other hard-to-treat conditions. However,
ethical issues and problems with regulations are also discussed in relation to CRISPR-based
therapies, which shows how important it is to use them safely and responsibly. As CRISPR continues
to change how drugs are made and used, this review shines a light on the amazing things that
have been done and what the future might hold in this rapidly changing field.
Potential Therapeutic Approach using Aromatic l-amino Acid
Decarboxylase and Glial-derived Neurotrophic Factor Therapy Targeting
Putamen in Parkinson's Disease
Authors: Tripathi Raman Kumar , Goyal Lav , Singh Shamsher 
Published: February 2024

Abstract::
Parkinson's disease (PD) is a neurodegenerative illness characterized by specific loss of
dopaminergic neurons, resulting in impaired motor movement. Its prevalence is twice as compared
to the previous 25 years and affects more than 10 million individuals. Lack of treatment still
uses levodopa and other options as disease management measures. Treatment shifts to gene therapy
(GT), which utilizes direct delivery of specific genes at the targeted area. Therefore, the use of
aromatic L-amino acid decarboxylase (AADC) and glial-derived neurotrophic factor (GDNF) therapy
achieves an effective control to treat PD. Patients diagnosed with PD may experience improved
therapeutic outcomes by reducing the frequency of drug administration while utilizing provasin
and AADC as dopaminergic protective therapy. Enhancing the enzymatic activity of tyrosine
hydroxylase (TH), glucocorticoid hormone (GCH), and AADC in the striatum would be useful
for external L-DOPA to restore the dopamine (DA) level. Increased expression of glutamic
acid decarboxylase (GAD) in the subthalamic nucleus (STN) may also be beneficial in PD. Targeting
GDNF therapy specifically to the putaminal region is clinically sound and beneficial in protecting
the dopaminergic neurons. Furthermore, preclinical and clinical studies supported the role of
GDNF in exhibiting its neuroprotective effect in neurological disorders. Another Ret receptor,
which belongs to the tyrosine kinase family, is expressed in dopaminergic neurons and sounds to
play a vital role in inhibiting the advancement of PD. GDNF binding on those receptors results in
the formation of a receptor-ligand complex. On the other hand, venous delivery of recombinant
GDNF by liposome-based and encapsulated cellular approaches enables the secure and effective
distribution of neurotrophic factors into the putamen and parenchyma. The current review emphasized
the rate of GT target GDNF and AADC therapy, along with the corresponding empirical evidence.
Role of MicroRNA in Hypoxic Tumours and their Potential as
Biomarkers for Early Detection of Cancer
Authors: Jayashree Pawar , Kalpita Mulye , Judith Talker , Singh Ahirwar Sonu , Ashwin Kotnis 
Published: February 2024

Abstract:
Hypoxia is a pathophysiological condition characterized by oxygen
deficiency in tissues, which negatively affects normal biological functions. It is a typical
microenvironment character of almost all solid tumours. Noncoding RNA are small
functional RNA molecules that regulate gene expression at chromatin and posttranscriptional
levels. Micro-RNAs (miRNAs) are a type of noncoding RNA and are
~12-22 nucleotides long that are crucial in regulating gene expression by partnering
with the mRNAs of protein-coding genes. It is widely reported that miRs play an
important role in various key processes and pathways during tumour formation, as well
as advancement in hypoxic tumors by influencing the HIF pathway. The role of
miRNAs in hypoxic tumours, namely in pancreatic, kidney, breast, lung and colorectal,
are described. These miRNAs have immense potential as diagnostic and prognostic
biomarkers for early cancer detection.
Pharmacological Activation of AMPK Prevents Drp1-mediated Mitochondrial Fission and Alleviates Hepatic Steatosis In vitro
Authors: Du Jingxia , Wang Tingting , Xiao Chengyao , Dong Yibo , Zhou Shiyao , Zhu Yujiao 
Published: February 2024

Background:
The incidence of non-alcoholic fatty liver disease (NAFLD) is
increasing worldwide. Adenosine monophosphate-activated protein kinase (AMPK)
activation is beneficial for NAFLD treatment. Recent studies show the excessive
fission of mitochondria during NAFLD progression, so targeting mitochondria dynamics
may be a possible target for NAFLD. Still, little is known about whether AMPK
regulates mitochondrial dynamics in hepar.

Objective:
This study investigated whether AMPK activation alleviates hepatic
steatosis by regulating mitochondrial dynamics mediated by GTPase dynamin-related
protein 1 (Drp1).

Methods:
Human hepatocyte line L-02 cells were cultured and subjected to palmitic
acid (PA) treatment for 24 h to establish a hepatic steatosis model in vitro, which was
pre-treated with different tool drugs. Hepatocyte function, hepatocyte lipid content,
mitochondrial reactive oxygen species (ROS) production, and mitochondrial
membrane potential (MMP) were examined. The expression levels of genes and
proteins associated with mitochondrial dynamics were assessed using reverse
transcription-quantitative PCR and western blotting.

Results:
The results indicated that 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside
(AICAR), an AMPK activator, improved hepatocyte function, as demonstrated
by decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
activity (P＜0.05 or P＜0.01). In addition, AICAR decreased total cholesterol (TC) and
triglyceride (TG) content and lipid deposition in hepatocytes (P＜0.01); decreased
ROS production; improved MMP (P＜0.01); reduced fission-1 (Fis1) and mitochondrial
fission factor (Mff) mRNA expression; and downregulated p-Drp1 (Ser 616) protein
expression. In contrast, AICAR increased mitochondrial fusion factor mitofusin-1
(Mfn1) and mitofusin-2 (Mfn2) mRNA expression and upregulated p-Drp1 (Ser 637)
protein expression. Mdivi-1, a Drp-1 inhibitor, was used to confirm whether
mitochondrial dynamics regulated by Drp1-mediated the role of AICAR. Similar to
AICAR, Mdivi-1 improved hepatocyte function and MMP significantly, decreased ROS
production and lipid deposition, downregulated Fis1 and Mff mRNA expression,
downregulated p-Drp1 (Ser 616) protein expression, and enhanced Mfn1 and Mfn2
mRNA and p-Drp1 (Ser 637) protein expression. However, Compound C, an AMPKspecific
inhibitor, had less impact on the protective effect of Mdivi-1.

Conclusion:
The results demonstrated that AMPK activation has a protective effect on
hepatic steatosis in vitro, largely dependent on the inhibition of Drp1-mediated
mitochondrial fission.
LKB1 Mutations Enhance Radiosensitivity in Non-Small Cell Lung Cancer Cells by Inducing G2/M Cell Cycle Phase Arrest
Authors: Yao Yuanhu , Qiu Xiangnan , Chen Meng , Qin Zhaohui , Zhang Xinjun , Zhang Wei 
Published: February 2024

Background:
Radiosensitivity remains an important factor affecting the
clinical outcome of radiotherapy for non-small cell lung cancer (NSCLC). Liver kinase
B1 (LKB1) as a tumor suppressor, is one of the most commonly mutated genes in
NSCLC. However, the role of LKB1 on radiosensitivity and the possible mechanism
have not been elucidated in the NSCLC. In this study, we investigated the regulatory
function of LKB1 in the radiosensitivity of NSCLC cells and its possible signaling
pathways.

Methods:
After regulating the expression of LKB1, cell proliferation was determined by
Cell Counting Kit-8 (CCK-8) assay. The flow cytometry assay was used to analyse cell
cycle distribution. Survival fraction and sensitization enhancement ratio (SER) were
generated by clonogenic survival assay. Western blot analysis was used to assess
expression levels of LKB1, p53, p21, γ-H2AX and p-Chk2.

Results:
Our study found that when the NSCLC cells were exposed to ionizing
radiation, LKB1 could inhibit NSCLC cell proliferation by promoting DNA double strand
break and inducing DNA repair. In addition, LKB1 could induce NSCLC cells G1 and
G2/M phase arrest through up-regulating expression of p53 and p21 proteins.

Conclusion:
This current study demonstrates that LKB1 enhances the radiosensitivity
of NSCLC cells via inhibiting NSCLC cell proliferation and inducing G2/M phase arrest,
and the mechanism of cell cycle arrest associated with signaling pathways of p53 and
p21 probably.
Preparation, Characterization, and Evaluation of Mesoporous Silica Nanoparticles in Enhancing Oral Bioavailability of Poorly Water-Soluble Drugs
Authors: Zhang Hong , Zuo Fanjiao , Wang Boyao , Qiu Xilong 
Published: February 2024

Background:
Breviscapine (BVP) is one of the extracts of several flavonoids of Erigeron
breviscapus, which has been widely used in the treatment of cerebral infarction and its sequelae,
cerebral thrombus, coronary heart disease, and angina pectoris. But BVP has poor solubility.

Objective:
The objective of the study is to develop mesoporous silica nanoparticles (MSNs) that can
be loaded with a drug with poor water solubility. The MSNs, which were designed for oral administration,
enhanced both the dissolution rate and drug loading capacity.

Methods:
The use of MSNs as an oral drug delivery system was investigated by SEM, TEM, BETBJH,
XRD, FT-IR, and HPLC. Additionally, we examined the oral bioavailability of BVP loaded
onto MSNs and examined the cellular cytotoxicity of MSNs.

Results:
The results indicate that the oral bioavailability of BVP after loading onto MSNs was greater
than that of a marketed product. Furthermore, we studied the mechanism by which MSNs enhance
the oral absorption of BVP.

Conclusion:
MSNs have the potential to enhance the oral bioavailability of poorly water-soluble
drugs by accelerating the drug dissolution rate.
Effective Strategies in Designing Chitosan-hyaluronic Acid Nanocarriers: From Synthesis to Drug Delivery Towards Chemotherapy
Authors: Hong Long-Quy , Ho Thao N.T , Cu Son T. , Ngan Lien Tuyet , Tran Ngoc Quyen , Dang Tien T. 
Published: February 2024

:
The biomedical field faces an ongoing challenge in developing more effective anti-cancer
medication due to the significant burden that cancer poses on human health. Extensive research has
been conducted on the utilization of natural polysaccharides in nanomedicine owing to their properties
of biocompatibility, biodegradability, non-immunogenicity, and non-toxicity. These characteristics
make them a potent drug delivery system for cancer therapy. The chitosan hyaluronic acid nanoparticle
(CSHANp) system, consisting of chitosan and hyaluronic acid nanoparticles, has exhibited
considerable potential as a nanocarrier for various cancer drugs, rendering it one of the most auspicious
systems presently accessible. The CSHANps demonstrate remarkable drug loading capacity,
precise control over drug release, and exceptional selectivity towards cancer cells. These properties
enhance the therapeutic effectiveness against cancerous cells. This article aims to provide a comprehensive
analysis of CSHANp, focusing on its characteristics, production techniques, applications, and
future prospects.
IR-780 Dye-based Targeting of Cancer-associated Fibroblasts Improves
Cancer Immunotherapy by Increasing Intra-tumoral T Lymphocytes
Infiltration
Authors: Yang Wei , Chen Zelin , Qu Langfan , Zhang Can , Chen Hongdan , Zheng Jiancheng , Chen Wanchao , Tan Xu , Shi Chunmeng 
Published: February 2024

Background::
Immune-checkpoint inhibitors (ICIs) against programmed death
(PD)-1/PD-L1 pathway immunotherapy have been demonstrated to be effective in only a subset of
patients with cancer, while the rest may exhibit low response or may develop drug resistance after
initially responding. Previous studies have indicated that extensive collagen-rich stroma secreted
by cancer-associated fibroblasts (CAFs) within the tumor microenvironment is one of the key obstructions
of the immunotherapy for some tumors by decreasing the infiltrating cytotoxic T cells.
However, there is still a lack of effective therapeutic strategies to control the extracellular matrix
by targeting CAFs.

Methods::
The enhanced uptake of IR-780 by CAFs was assessed by using in vivo or ex vivo nearinfrared
fluorescence imaging, confocal NIR fluorescent imaging, and CAFs isolation testing. The
fibrotic phenotype down-regulation effects and in vitro CAFs killing effect of IR-780 were tested
by qPCR, western blot, and flow cytometry. The in vivo therapeutic enhancement of anti-PD-L1
by IR-780 was evaluated on EMT6 and MC38 subcutaneous xenograft mice models.

Results::
IR-780 has been demonstrated to be preferentially taken up by CAFs and accumulate in
the mitochondria. Further results identified low-dose IR-780 to downregulate the fibrotic phenotype,
while high-dose IR-780 could directly kill both CAFs and EMT6 cells in vitro. Moreover,
IR-780 significantly inhibited extracellular matrix (ECM) protein deposition in the peri-tumoral
stroma on subcutaneous EMT6 and MC38 xenografts, which increased the proportion of tumor-infiltrating
lymphocytes (TILs) in the deep tumor and further promoted anti-PD-L1 therapeutic efficacy.

Conclusion::
This work provides a unique strategy for the inhibition of ECM protein deposition in
the tumor microenvironment by targeted regulating of CAFs, which destroys the T cell barrier and
further promotes tumor response to PD-L1 monoclonal antibody. IR-780 has been proposed as a
potential therapeutic small-molecule adjuvant to promote the effect of immunotherapy.
Neuroinflammation in Glioblastoma: The Role of the Microenvironment
in Tumour Progression
Authors: Nóbrega Ana Helena Larangeira , Pimentel Rafael Sampaio , Prado Ana Paula , Garcia Jenifer , Frozza Rudimar Luiz , Bernardi Andressa 
Published: February 2024

Abstract:
Glioblastoma (GBM) stands as the most aggressive and lethal among the main types of
primary brain tumors. It exhibits malignant growth, infiltrating the brain tissue, and displaying resistance
toward treatment. GBM is a complex disease characterized by high degrees of heterogeneity.
During tumour growth, microglia and astrocytes, among other cells, infiltrate the tumour microenvironment
and contribute extensively to gliomagenesis. Tumour-associated macrophages
(TAMs), either of peripheral origin or representing brain-intrinsic microglia, are the most numerous
nonneoplastic populations in the tumour microenvironment in GBM. The complex heterogeneous
nature of GBM cells is facilitated by the local inflammatory tumour microenvironment,
which mostly induces tumour aggressiveness and drug resistance. The immunosuppressive tumour
microenvironment of GBM provides multiple pathways for tumour immune evasion, contributing
to tumour progression. Additionally, TAMs and astrocytes can contribute to tumour progression
through the release of cytokines and activation of signalling pathways. In this review, we summarize
the role of the microenvironment in GBM progression, focusing on neuroinflammation. These
recent advancements in research of the microenvironment hold the potential to offer a promising
approach to the treatment of GBM in the coming times.
The Effects of Mesenchymal Stem Cells Loaded with Oncolytic
Coxsackievirus A21 on Mouse Models of Colorectal Cancer
Authors: Karbalaee Reza , Mehdizadeh Saber , Ghaleh Hadi Esmaeili Gouvarchin , Izadi Morteza , Kondori Bahman Jalali , Dorostkar Ruhollah , Hosseini Seyed Morteza 
Published: February 2024

Background:
Cancer is a major cause of death worldwide. Colorectal cancer is the second
most common type. Additional treatments like chemotherapy and radiation therapy may be
recommended. Developing new techniques is vital due to drug resistance and a lack of targeted
therapies.

Objective:
In this study, the effects of mesenchymal stem cells (MSCs) loaded with oncolytic Coxsackievirus
A21 (CVA21) on a mouse model of CRC were investigated.

Methods:
The therapeutic potency of MSCs loaded with oncolytic CVA21 were evaluated in an
experimental mouse model of colorectal cancer which received an injection CT26 cells per mouse
subcutaneously. Splenocyte proliferation index, lactate dehydrogenase (LDH) assay, nitric oxide
(NO) production assessment, and cytokine assay (IFN-γ, IL-4, IL-10, and TGF-β) in the splenocyte
supernatant were all used to evaluate the impact of MSCs loaded with CVA21.

Results:
The results of this study showed that the treatment of a mouse model of colorectal cancer
with MSCs loaded with oncolytic CVA21 could significantly suppress the tumor growth, which
was accompanied by stimulation of splenocytes proliferation index, an increase of NO and LDH.
Also, MSCs loaded with oncolytic CVA21 increased the secretion of IFN-γ and decreased the secretion
of IL-4, IL-10, and TGF-β.

Conclusion:
The results of the current study suggest that MSCs loaded with oncolytic CVA21
therapy for the CRC mouse model may have some potential advantages. On the other hand, the results
of the study showed that, in addition to activating the acquired immune system, the use of
MSCs loaded with oncolytic CVA21 also stimulates the innate immune system by increasing level
of nitric oxide.
Brucine Inhibits Proliferation of Pancreatic Ductal Adenocarcinoma
through PI3K/AKT Pathway-induced Mitochondrial Apoptosis
Authors: Wu You , Zhang Fenglin , Xu Panling , Li Ping 
Published: February 2024

Introduction:
The purpose of this research was to settle the role of brucine in pancreatic
ductal adenocarcinoma (PDAC) and the mechanisms involved.

Methods:
The findings of this study suggest that brucine exerts inhibitory effects on cell growth,
clonogenicity, and invasive potential of Panc02 and Mia Paca-2 cells. These effects may be linked
to an increase in apoptotic-prone cell population.

Results:
Gene sequencing data suggests that these effects are mediated through the induction of
apoptosis. Experimental evidence further supports the notion that brucine reduces mitochondrial
membrane potential and upregulates Bax expression while downregulating Bcl-2 expression. These
effects are believed to be a result of brucine-mediated suppression of PI3K/Akt activity, which
serves as a regulatory factor of mTOR, Bax, and Bcl-2. Suppression of PI3K activity enhances the
tumor-suppressing effects of brucine.

Conclusion:
Overall, these findings suggest that brucine has therapeutic potential as a remedy option
for PDAC.
Effect of Neoadjuvant Immunotherapy Combined with Chemotherapy on
Pulmonary Function and Postoperative Pulmonary Complications in
Esophageal Cancer: A Retrospective Study
Authors: Gao Yongyin , Zhang Hongdian , Qiu Yanli , Bian Xueyan , Wang Xue , Li Yue 
Published: February 2024

Background:
Neoadjuvant immunotherapy, targeting the PD-1 or PD-L1, combined
with chemotherapy (NICT), can improve the radical resection and survival rates for locally advanced
EC. However, it may impair pulmonary function, and the effect of NICT on pulmonary
function and postoperative pulmonary complications in EC patients remains unknown. This study
aimed to investigate whether NICT can affect pulmonary functions and postoperative pulmonary
complications in EC patients.

Methods:
The study retrospectively recruited 220 EC patients who received NICT at the Department
of Esophageal Cancer in Tianjin Medical University Cancer Institute & Hospital from January
2021 to June 2022. Changes in pulmonary function before and after NICT were compared.
Logistic regression analysis was performed to analyze the correlations of pulmonary functions and
clinical characteristics with postoperative pulmonary complications, respectively.

Results:
The FEV1% pred, FVC, FVC% pred, and FEV1/FVC% significantly increased after
NICT, with a P-value of 0.018, 0.005, 0.001, and 0.036, respectively. In contrast, there was a significant
decline in the DLCO (8.92 ± 2.34 L before NICT vs. 7.79 ± 2.30 L after NICT; P < 0.05)
and DLCO% pred (102.97 ± 26.22% before NICT vs. 90.18 ± 25.04% after NICT; P < 0.05).
High DLCO and DLCO% pred at baseline levels were risk factors for DLCO reduction in EC patients
after NICT. Advanced age, smoking history, FEV1% pred after NICT, and FVC% pred baseline
and after therapy were risk factors for postoperative pulmonary complications, with a P-value
of 0.043, 0.038, 0.048, 0.034, and 0.004, respectively. Although the DLCO level decreased after
NICT, it did not increase the incidence of postoperative pulmonary complications.

Conclusion:
NICT may improve pulmonary ventilation function but also lead to a decrease in DLCO
and DLCO% pred in EC patients. Nevertheless, the decreased DLCO after NICT did not increase
the risk of postoperative pulmonary complications.