bluuebunny/crossref_metadata_2025 huggingface dataset:
Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53
Authors: Tang Yuan-juan , Zhang Zhen , Yan Tong , Chen Ken , Xu Guo-fan , Xiong Shi-qiang , Wu Dai-qian , Chen Jie , Jose Pedro A. , Zeng Chun-yu , Fu Jin-juan
Published: April 2024

Background

Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia–reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known.

Methods and results

T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose.

Conclusion

This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.
The neutrophil-to-lymphocyte ratio is associated with all-cause and cardiovascular mortality among individuals with hypertension
Authors: Zhang Xuexue , Wei Rui , Wang Xujie , Zhang Wantong , Li Mengxuan , Ni Tian , Weng Weiliang , Li Qiuyan
Published: April 2024

Background

Identifying reliable prognostic markers is crucial for the effective management of hypertension. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential inflammatory marker linked to cardiovascular outcomes. This study aims to investigate the association of NLR with all-cause and cardiovascular mortality among patients with hypertension.

Methods

This study analyzed data from 3067 hypertensive adults in the National Health and Nutritional Examination Surveys (NHANES) from 2009 to 2014. Mortality details were obtained from the National Death Index (NDI). Restricted cubic spline (RCS) was deployed to visualize the association of the NLR with mortality risk. Weighted Cox proportional hazards models were employed to assess the independent association of NLR with mortality risk. Time-dependent receiver operating characteristic curve (ROC) analysis was conducted to access the predictive ability of NLR for survival. Mediation analysis was used to explore the indirect impact of NLR on mortality mediated through eGFR.

Results

Over a median 92.0-months follow-up, 538 deaths occurred, including 114 cardiovascular deaths. RCS analysis revealed a positive association between NLR and both all-cause and cardiovascular mortality. Participants were stratified into higher (> 3.5) and lower (≤ 3.5) NLR groups. Weighted Cox proportional hazards models demonstrated that individuals with higher NLR had a significantly increased risk of all-cause (HR 1.96, 95% confidence interval (CI) 1.52–2.52, p < 0.0001) and cardiovascular mortality (HR 2.33, 95% CI 1.54–3.51, p < 0.0001). Stratified and interaction analysis confirmed the stability of the core results. Notably, eGFR partially mediated the association between NLR and both all-cause and cardiovascular mortality by a 5.4% and 4.7% proportion, respectively. Additionally, the areas under the curve (AUC) of the 3-, 5- and 10- year survival was 0.68, 0.65 and 0.64 for all-cause mortality and 0.68, 0.70 and 0.69 for cardiovascular mortality, respectively.

Conclusion

Elevated NLR independently confers an increased risk for both all-cause and cardiovascular mortality in individuals with hypertension.
The association of atherogenic index of plasma with cardiovascular outcomes in patients with coronary artery disease: A systematic review and meta-analysis
Authors: Rabiee Rad Mehrdad , Ghasempour Dabaghi Ghazal , Darouei Bahar , Amani-Beni Reza
Published: April 2024

Background

Atherogenic index of plasma (AIP) represents a novel marker in the current era of cardiovascular diseases. In this meta-analysis, we aimed to evaluate the association of AIP with cardiovascular prognosis in patients with coronary artery disease (CAD).

Methods

PubMed, Scopus, and Web of Science databases were searched from inception through 2024. The primary outcome was major cardiovascular events (MACE). The secondary outcomes included all-causes death, cardiovascular death, myocardial infarction (MI), stroke, revascularization, and no-reflow phenomenon. AIP was determined by taking the logarithm of the ratio of triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C). The data analysis was represented using the risk ratio (RR) along with a 95% confidence interval (CI).

Results

Sixteen studies with a total number of 20,833 patients met the eligible criteria. The pooled-analysis showed a significant increased risk of MACE in the highest AIP group compared with the lowest AIP group (RR = 1.63; 95% CI, 1.44–1.85; P < 0.001). A similar result was observed when AIP was regarded as a continuous variable (RR = 1.54; 95% CI, 1.30–1.83; P < 0.001). Besides, elevated AIP was associated with increased risk of cardiovascular death (RR = 1.79; 95% CI, 1.09–2.78; P = 0.02), MI (RR = 2.21; 95% CI, 1.55–3.13; P < 0.001), revascularization (RR = 1.62; 95% CI, 1.34–1.97; P < 0.001), no-reflow phenomenon (RR = 3.12 95% CI, 1.09–8.96; P = 0.034), and stent thrombosis (RR = 13.46; 95%CI, 1.39-129.02; P = 0.025). However, AIP was not significantly associated with the risk of all-causes death and stroke among patients with CAD.

Conclusions

The results of this study demonstrated that increased AIP is an independent prognostic factors in patients with CAD. Further research is warranted to elucidate the potential development of targeted interventions to modify AIP levels and improve patient outcomes.
Association of birth weight with type 2 diabetes mellitus and the mediating role of fatty acids traits: a two-step mendelian randomization study
Authors: Cao Limin , Wen Yahui , Fan Keyi , Wang Qiwei , Zhang Yaochen , Li Zhenglong , Wang Nan , Zhang Xinhua
Published: April 2024

Background

Observational studies have suggested an association between birth weight and type 2 diabetes mellitus, but the causality between them has not been established. We aimed to obtain the causal relationship between birth weight with T2DM and quantify the mediating effects of potential modifiable risk factors.

Methods

Two-step, two-sample Mendelian randomization (MR) techniques were applied using SNPs as genetic instruments for exposure and mediators. Summary data from genome-wide association studies (GWAS) for birth weight, T2DM, and a series of fatty acids traits and their ratios were leveraged. The inverse variance weighted (IVW) method was the main analysis approach. In addition, the heterogeneity test, horizontal pleiotropy test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, and leave-one-out analysis were carried out to assess the robustness.

Results

The IVW method showed that lower birth weight raised the risk of T2DM (β: −1.113, 95% CI: −1.573 ∼ −0.652). Two-step MR identified 4 of 17 candidate mediators partially mediating the effect of lower birth weight on T2DM, including ratio of polyunsaturated fatty acids to monounsaturated fatty acids (proportion mediated: 7.9%), ratio of polyunsaturated fatty acids to total fatty acids (7.2%), ratio of omega-6 fatty acids to total fatty acids (8.1%) and ratio of linoleic acid to total fatty acids ratio (6.0%).

Conclusions

Our findings supported a potentially causal effect of birth weight against T2DM with considerable mediation by modifiable risk factors. Interventions that target these factors have the potential to reduce the burden of T2DM attributable to low birth weight.
MiR26a reverses enzalutamide resistance in a bone-tumor targeted system with an enhanced effect on bone metastatic CRPC
Authors: Wang Yuanyuan , Chen Jiyuan , Gong Luyao , Wang Yunxia , Siltari Aino , Lou Yan-Ru , Murtola Teemu J. , Gao Shen , Gao Yuan
Published: April 2024

Resistance to androgen receptor (AR) inhibitors, including enzalutamide (Enz), as well as bone metastasis, are major challenges for castration-resistant prostate cancer (CRPC) treatment. In this study, we identified that miR26a can restore Enz sensitivity and inhibit bone metastatic CRPC. To achieve the highest combination effect of miR26a and Enz, we developed a cancer-targeted nano-system (Bm@PT/Enz-miR26a) using bone marrow mesenchymal stem cell (BMSC) membrane and T140 peptide to co-deliver Enz and miR26a. The in vitro/in vivo results demonstrated that miR26a can reverse Enz resistance and synergistically shrink tumor growth, invasion, and metastasis (especially secondary metastasis) in both subcutaneous and bone metastatic CRPC mouse models. We also found that the EZH2/SFRP1/WNT5A axis may be involved in this role. These findings open new avenues for treating bone metastatic and Enz-resistant CRPC.
Reproductive outcomes of dual trigger therapy with GnRH agonist and hCG versus hCG trigger in women with diminished ovarian reserve: a retrospective study
Authors: Chen Kai , Zhang Chunmei , Chen Lixue , Zhao Yue , Li Hongzhen
Published: April 2024

Background

Diminished ovarian reserve (DOR) is one of the obstacles affecting the reproductive outcomes of patients receiving assisted reproductive therapy. The purpose of this study was to investigate whether dual trigger, including gonadotropin‐releasing hormone agonist (GnRHa) and human chorionic gonadotropin (hCG), can improve pregnancy outcomes in patients with DOR undergoing in vitro fertilization (IVF) cycles using mild stimulation protocols.

Methods

A total of 734 patients with DOR were included in this retrospective study. Patients were divided into a recombinant hCG trigger group and a dual trigger group (hCG combined with GnRHa) according to the different trigger drugs used. The main outcome measures included the number of oocytes retrieved, the fertilization rate, the number of transferable embryos, the implantation rate, the clinical pregnancy rate, the miscarriage rate, the live birth rate (LBR), and the cumulative live birth rate (CLBR). Generalized linear model and logistic regression analyses were performed for confounding factors.

Results

There were 337 cycles with a single hCG trigger and 397 cycles with dual trigger. The dual trigger group demonstrated significantly higher numbers of retrieved oocytes [3.60 vs. 2.39, adjusted β = 0.538 (0.221–0.855)], fertilized oocytes [2.55 vs. 1.94, adjusted β = 0.277 (0.031–0.523)] and transferable embryos [1.22 vs. 0.95, adjusted β = 0.162 (-0.005–0.329)] than did the hCG trigger group, whereas no significant difference in the fertilization rate was observed between the two groups. Moreover, the embryo transfer cancellation rate (35.5% vs. 43.9%) was obviously lower in the dual trigger group. Among the fresh embryo transfer cycles, the implantation rate, clinical pregnancy rate, miscarriage rate and live birth rate were similar between the two groups. After controlling for potential confounding variables, the trigger method was identified as an independent factor affecting the number of oocytes retrieved but had no significant impact on the CLBR.

Conclusions

Dual triggering of final oocyte maturation with hCG combined with GnRHa can significantly increase the number of oocytes retrieved in patients with DOR but has no improvement effect on the implantation rate, clinical pregnancy rate or LBR of fresh cycles or on the CLBR.
Towards universal health coverage in Vietnam: a mixed-method case study of enrolling people with tuberculosis into social health insurance
Authors: Forse Rachel , Yoshino Clara Akie , Nguyen Thanh Thi , Phan Thi Hoang Yen , Vo Luan N. Q. , Codlin Andrew J. , Nguyen Lan , Hoang Chi , Basu Lopa , Pham Minh , Nguyen Hoa Binh , Van Dinh Luong , Caws Maxine , Wingfield Tom , Lönnroth Knut , Sidney-Annerstedt Kristi
Published: April 2024

Background

Vietnam’s primary mechanism of achieving sustainable funding for universal health coverage (UHC) and financial protection has been through its social health insurance (SHI) scheme. Steady progress towards access has been made and by 2020, over 90% of the population were enrolled in SHI. In 2022, as part of a larger transition towards the increased domestic financing of healthcare, tuberculosis (TB) services were integrated into SHI. This change required people with TB to use SHI for treatment at district-level facilities or to pay out of pocket for services. This study was conducted in preparation for this transition. It aimed to understand more about uninsured people with TB, assess the feasibility of enrolling them into SHI, and identify the barriers they faced in this process.

Methods

A mixed-method case study was conducted using a convergent parallel design between November 2018 and January 2022 in ten districts of Hanoi and Ho Chi Minh City, Vietnam. Quantitative data were collected through a pilot intervention that aimed to facilitate SHI enrollment for uninsured individuals with TB. Descriptive statistics were calculated. Qualitative interviews were conducted with 34 participants, who were purposively sampled for maximum variation. Qualitative data were analyzed through an inductive approach and themes were identified through framework analysis. Quantitative and qualitative data sources were triangulated.

Results

We attempted to enroll 115 uninsured people with TB into SHI; 76.5% were able to enroll. On average, it took 34.5 days to obtain a SHI card and it cost USD 66 per household. The themes indicated that a lack of knowledge, high costs for annual premiums, and the household-based registration requirement were barriers to SHI enrollment. Participants indicated that alternative enrolment mechanisms and greater procedural flexibility, particularly for undocumented people, is required to achieve full population coverage with SHI in urban centers.

Conclusions

Significant addressable barriers to SHI enrolment for people affected by TB were identified. A quarter of individuals remained unable to enroll after receiving enhanced support due to lack of required documentation. The experience gained during this health financing transition is relevant for other middle-income countries as they address the provision of financial protection for the treatment of infectious diseases.
SUMOylation of annexin A6 retards cell migration and tumor growth by suppressing RHOU/AKT1–involved EMT in hepatocellular carcinoma
Authors: Yang Yanfang , Huang Lan , Zhang Nan , Deng Ya-Nan , Cao Xu , Liang Yue , Hou Huijin , Luo Yinheng , Yang Yang , Li Qiu , Liang Shufang
Published: April 2024

Background

The protein annexin A6 (AnxA6) is involved in numerous membrane-related biological processes including cell migration and invasion by interacting with other proteins. The dysfunction of AnxA6, including protein expression abundance change and imbalance of post-translational modification, is tightly related to multiple cancers. Herein we focus on the biological function of AnxA6 SUMOylation in hepatocellular carcinoma (HCC) progression.

Methods

The modification sites of AnxA6 SUMOylation were identified by LC-MS/MS and amino acid site mutation. AnxA6 expression was assessed by immunohistochemistry and immunofluorescence. HCC cells were induced into the epithelial-mesenchymal transition (EMT)-featured cells by 100 ng/mL 12-O-tetradecanoylphorbol-13-acetate exposure. The ability of cell migration was evaluated under AnxA6 overexpression by transwell assay. The SUMO1 modified AnxA6 proteins were enriched from total cellular proteins by immunoprecipitation with anti-SUMO1 antibody, then the SUMOylated AnxA6 was detected by Western blot using anti-AnxA6 antibody. The nude mouse xenograft and orthotopic hepatoma models were established to determine HCC growth and tumorigenicity in vivo. The HCC patient’s overall survival versus AnxA6 expression level was evaluated by the Kaplan–Meier method.

Results

Lys579 is a major SUMO1 modification site of AnxA6 in HCC cells, and SUMOylation protects AnxA6 from degradation via the ubiquitin-proteasome pathway. Compared to the wild-type AnxA6, its SUMO site mutant AnxA6K579R leads to disassociation of the binding of AnxA6 with RHOU, subsequently RHOU-mediated p-AKT1ser473 is upregulated to facilitate cell migration and EMT progression in HCC. Moreover, the SENP1 deSUMOylates AnxA6, and AnxA6 expression is negatively correlated with SENP1 protein expression level in HCC tissues, and a high gene expression ratio of ANXA6/SENP1 indicates a poor overall survival of patients.

Conclusions

AnxA6 deSUMOylation contributes to HCC progression and EMT phenotype, and the combination of AnxA6 and SENP1 is a better tumor biomarker for diagnosis of HCC grade malignancy and prognosis.
Endogenous estrogen metabolites as oxidative stress mediators and endometrial cancer biomarkers
Authors: Bukato Katarzyna , Kostrzewa Tomasz , Gammazza Antonella Marino , Gorska-Ponikowska Magdalena , Sawicki Sambor
Published: April 2024

Background

Endometrial cancer is the most common gynecologic malignancy found in developed countries. Because therapy can be curative at first, early detection and diagnosis are crucial for successful treatment. Early diagnosis allows patients to avoid radical therapies and offers conservative management options. There are currently no proven biomarkers that predict the risk of disease occurrence, enable early identification or support prognostic evaluation. Consequently, there is increasing interest in discovering sensitive and specific biomarkers for the detection of endometrial cancer using noninvasive approaches.

Content

Hormonal imbalance caused by unopposed estrogen affects the expression of genes involved in cell proliferation and apoptosis, which can lead to uncontrolled cell growth and carcinogenesis. In addition, due to their ability to cause oxidative stress, estradiol metabolites have both carcinogenic and anticarcinogenic properties. Catechol estrogens are converted to reactive quinones, resulting in oxidative DNA damage that can initiate the carcinogenic process. The molecular anticancer mechanisms are still not fully understood, but it has been established that some estradiol metabolites generate reactive oxygen species and reactive nitrogen species, resulting in nitro-oxidative stress that causes cancer cell cycle arrest or cell death. Therefore, identifying biomarkers that reflect this hormonal imbalance and the presence of endometrial cancer in minimally invasive or noninvasive samples such as blood or urine could significantly improve early detection and treatment outcomes.
Single cell analysis reveals the roles and regulatory mechanisms of type-I interferons in Parkinson’s disease
Authors: Quan Pusheng , Li Xueying , Si Yao , Sun Linlin , Ding Fei Fan , Fan Yuwei , Liu Han , Wei Chengqun , Li Ruihua , Zhao Xue , Yang Fan , Yao Lifen
Published: April 2024

The pathogenesis of Parkinson’s disease (PD) is strongly associated with neuroinflammation, and type I interferons (IFN-I) play a crucial role in regulating immune and inflammatory responses. However, the specific features of IFN in different cell types and the underlying mechanisms of PD have yet to be fully described. In this study, we analyzed the GSE157783 dataset, which includes 39,024 single-cell RNA sequencing results for five PD patients and six healthy controls from the Gene Expression Omnibus database. After cell type annotation, we intersected differentially expressed genes in each cell subcluster with genes collected in The Interferome database to generate an IFN-I-stimulated gene set (ISGs). Based on this gene set, we used the R package AUCell to score each cell, representing the IFN-I activity. Additionally, we performed monocle trajectory analysis, and single-cell regulatory network inference and clustering (SCENIC) to uncover the underlying mechanisms. In silico gene perturbation and subsequent experiments confirm NFATc2 regulation of type I interferon response and neuroinflammation. Our analysis revealed that microglia, endothelial cells, and pericytes exhibited the highest activity of IFN-I. Furthermore, single-cell trajectory detection demonstrated that microglia in the midbrain of PD patients were in a pro-inflammatory activation state, which was validated in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model as well. We identified transcription factors NFATc2, which was significantly up-regulated and involved in the expression of ISGs and activation of microglia in PD. In the 1-Methyl-4-phenylpyridinium (MPP+)-induced BV2 cell model, the suppression of NFATc2 resulted in a reduction in IFN-β levels, impeding the phosphorylation of STAT1, and attenuating the activation of the NF-κB pathway. Furthermore, the downregulation of NFATc2 mitigated the detrimental effects on SH-SY5Y cells co-cultured in conditioned medium. Our study highlights the critical role of microglia in type I interferon responses in PD. Additionally, we identified transcription factors NFATc2 as key regulators of aberrant type I interferon responses and microglial pro-inflammatory activation in PD. These findings provide new insights into the pathogenesis of PD and may have implications for the development of novel therapeutic strategies.
Double-negative T cells ameliorate psoriasis by selectively inhibiting IL-17A-producing γδlow T cells
Authors: Wei Yunxiong , Sun Guangyong , Yang Yang , Li Mingyang , Zheng Shimeng , Wang Xiyu , Zhong Xinjie , Zhang Zihan , Han Xiaotong , Cheng Haiyan , Zhang Dong , Mei Xueling
Published: April 2024

Background

Psoriasis is a chronic immune-mediated skin condition. Although biologic treatments are effective in controlling psoriasis, some patients do not respond or lose response to these therapies. Thus, new strategies for psoriasis treatment are still urgently needed. Double-negative T cells (DNT) play a significant immunoregulatory role in autoimmune diseases. In this study, we aimed to evaluate the protective effect of DNT in psoriasis and explore the underlying mechanism.

Methods

We conducted a single adoptive transfer of DNT into an imiquimod (IMQ)-induced psoriasis mouse model through tail vein injection. The skin inflammation and IL-17A producing γδ T cells were evaluated.

Results

DNT administration significantly reduced the inflammatory response in mouse skin, characterized by decreased skin folds, scales, and red patches. After DNT treatment, the secretion of IL-17A by RORc+ γδlow T cells in the skin was selectively suppressed, resulting in an amelioration of skin inflammation. Transcriptomic data suggested heightened expression of NKG2D ligands in γδlow T cells within the mouse model of psoriasis induced by IMQ. When blocking the NKG2D ligand and NKG2D (expressed by DNT) interaction, the cytotoxic efficacy of DNT against RORc+IL17A+ γδlow T cells was attenuated. Using Ccr5−/− DNT for treatment yielded evidence that DNT migrates into inflamed skin tissue and fails to protect IMQ-induced skin lesions.

Conclusions

DNT could migrate to inflamed skin tissue through CCR5, selectively inhibit IL-17-producing γδlow T cells and finally ameliorate mouse psoriasis. Our study provides feasibility for using immune cell therapy for the prevention and treatment of psoriasis in the clinic.
Micro- and nanoplastics concepts for particle and fibre toxicologists
Authors: Wright Stephanie , Cassee Flemming R. , Erdely Aaron , Campen Matthew J.
Published: April 2024

Micro- and nanoplastic particles (MNP) are omnipresent as either pollution or intentionally used in consumer products, released from packaging or even food. There is an exponential increase in the production of plastics. With the realization of bioaccumulation in humans, toxicity research is quickly expanding. There is a rapid increase in the number of papers published on the potential implications of exposure to MNP which necessitates a call for quality criteria to be applied when doing the research. At present, most papers on MNP describe the effects of commercially available polymer (mostly polystyrene) beads that are typically not the MNP of greatest concern. This is not a fault of the research community, necessarily, as the MNPs to which humans are exposed are usually not available in the quantities needed for toxicological research and innovations are needed to supply environmentally-relevant MNP models. In addition, like we have learned from decades of research with particulate matter and engineered nanomaterials, sample physicochemical characteristics and preparation can have major impacts on the biological responses and interpretation of the research findings. Lastly, MNP dosimetry may pose challenges as (1) we are seeing early evidence that plastics are already in the human body at quite high levels that may be difficult to achieve in acute in vitro studies and (2) plastics are already in the diets fed to preclinical models. This commentary highlights the pitfalls and recommendations for particle and fibre toxicologists that should be considered when performing and disseminating the research.
Clinical efficacy and imaging analysis of oblique lateral lumbar interbody fusion in the treatment of different types of lumbar intervertebral foramen stenosis
Authors: Gao Yuan , Liu Fengyu , Gu Zhenfang , Zhao Zhengqi , Liu Yanbing , Lu Kuan , Sun Xianze
Published: April 2024

Purpose

To analyze and study the clinical efficacy and imaging indexes of oblique lateral lumbar interbody fusion (OLIF) in the treatment of lumbar intervertebral foramen stenosis(LFS) caused by different causes.

Method

33 patients with LFS treated with OLIF from January 2018 to May 2022 were reviewed. Oswestry Dysfunction Index (ODI) and visual analogue scale (VAS) were calculated before and after operation. Segmental lordotic angle (SLA), lumbar lordotic angle (LLA) and segmental scoliosis angle (SSA), disc height (DH), posterior disc height (PDH), lateral disc height (LDH), foraminal height (FH), foramen width (FW) and foraminal cross-sectional area (FSCA) were measured before and after operation.

Result

The VAS and ODI after operation were significantly improved as compared with those before operation. Compared with pre-operation, the DH, PHD increased by 67.6%, 94.6%, LDH increased by 107.4% (left), 101.7% (right), and FH increased by 30.2% (left), 34.5% (right). The FSCA increased by 93.1% (left), 89.0% (right), and the FW increased by 137.0% (left), 149.6% (right). The postoperative SSA was corrected by 74.5%, the postoperative SLA, LLA were corrected by 70.2%, 38.1%, respectively. All the imaging indexes were significantly improved (p < 0.01).

Conclusion

The clinical efficacy and imaging data of OLIF in the treatment of LFS caused by low and moderate lumbar spondylolisthesis, intervertebral disc bulge and reduced intervertebral space height, degenerative lumbar scoliosis, articular process hyperplasia or dislocation have been well improved. OLIF may be one of the better surgical treatments for LFS caused by the above conditions.
Time-dependent complexity characterisation of activity patterns in patients with Chronic Fatigue Syndrome
Authors: Rabaey Paloma , Decat Peter , Heytens Stefan , Vogelaers Dirk , Mariman An , Demeester Thomas
Published: April 2024

Background

Chronic Fatigue Syndrome patients suffer from symptoms that cannot be explained by a single underlying biological cause. It is sometimes claimed that these symptoms are a manifestation of a disrupted autonomic nervous system. Prior works studying this claim from the complex adaptive systems perspective, have observed a lower average complexity of physical activity patterns in chronic fatigue syndrome patients compared to healthy controls. To further study the robustness of such methods, we investigate the within-patient changes in complexity of activity over time. Furthermore, we explore how these changes might be related to changes in patient functioning.

Methods

We propose an extension of the allometric aggregation method, which characterises the complexity of a physiological signal by quantifying the evolution of its fractal dimension. We use it to investigate the temporal variations in within-patient complexity. To this end, physical activity patterns of 7 patients diagnosed with chronic fatigue syndrome were recorded over a period of 3 weeks. These recordings are accompanied by physicians’ judgements in terms of the patients’ weekly functioning.

Results

We report significant within-patient variations in complexity over time. The obtained metrics are shown to depend on the range of timescales for which these are evaluated. We were unable to establish a consistent link between complexity and functioning on a week-by-week basis for the majority of the patients.

Conclusions

The considerable within-patient variations of the fractal dimension across scales and time force us to question the utility of previous studies that characterise long-term activity signals using a single static complexity metric. The complexity of a Chronic Fatigue Syndrome patient’s physical activity signal does not suffice to characterise their high-level functioning over time and has limited potential as an objective monitoring metric by itself.
Transcriptional regulation of cancer stem cell: regulatory factors elucidation and cancer treatment strategies
Authors: Zhang Zhengyue , Zhang Yanjie
Published: April 2024

Cancer stem cells (CSCs) were first discovered in the 1990s, revealing the mysteries of cancer origin, migration, recurrence and drug-resistance from a new perspective. The expression of pluripotent genes and complex signal regulatory networks are significant features of CSC, also act as core factors to affect the characteristics of CSC. Transcription is a necessary link to regulate the phenotype and potential of CSC, involving chromatin environment, nucleosome occupancy, histone modification, transcription factor (TF) availability and cis-regulatory elements, which suffer from ambient pressure. Especially, the expression and activity of pluripotent TFs are deeply affected by both internal and external factors, which is the foundation of CSC transcriptional regulation in the current research framework. Growing evidence indicates that regulating epigenetic modifications to alter cancer stemness is effective, and some special promoters and enhancers can serve as targets to influence the properties of CSC. Clarifying the factors that regulate CSC transcription will assist us directly target key stem genes and TFs, or hinder CSC transcription through environmental and other related factors, in order to achieve the goal of inhibiting CSC and tumors. This paper comprehensively reviews the traditional aspects of transcriptional regulation, and explores the progress and insights of the impact on CSC transcription and status through tumor microenvironment (TME), hypoxia, metabolism and new meaningful regulatory factors in conjunction with the latest research. Finally, we present opinions on omnidirectional targeting CSCs transcription to eliminate CSCs and address tumor resistance.
Sialyl-Tn serves as a potential therapeutic target for ovarian cancer
Authors: Al-Alem Linah , Prendergast Jillian M. , Clark Justin , Zarrella Bianca , Zarrella Dominique T. , Hill Sarah J. , Growdon Whitfield B. , Pooladanda Venkatesh , Spriggs David R. , Cramer Daniel , Elias Kevin M. , Nazer Rawan I. , Skates Steven J. , Behrens Jeff , Dransfield Daniel T. , Rueda Bo R.
Published: April 2024

Background

Ovarian cancer remains the deadliest of the gynecologic cancers in the United States. There have been limited advances in treatment strategies that have seen marked increases in overall survival. Thus, it is essential to continue developing and validating new treatment strategies and markers to identify patients who would benefit from the new strategy. In this report, we sought to further validate applications for a novel humanized anti-Sialyl Tn antibody-drug conjugate (anti-STn-ADC) in ovarian cancer.

Methods

We aimed to further test a humanized anti-STn-ADC in sialyl-Tn (STn) positive and negative ovarian cancer cell line, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. Furthermore, we sought to determine whether serum STn levels would reflect STn positivity in the tumor samples enabling us to identify patients that an anti-STn-ADC strategy would best serve. We developed a custom ELISA with high specificity and sensitivity, that was used to assess whether circulating STn levels would correlate with stage, progression-free survival, overall survival, and its value in augmenting CA-125 as a diagnostic. Lastly, we assessed whether the serum levels reflected what was observed via immunohistochemical analysis in a subset of tumor samples.

Results

Our in vitro experiments further define the specificity of the anti-STn-ADC. The ovarian cancer PDO, and PDX models provide additional support for an anti-STn-ADC-based strategy for targeting ovarian cancer. The custom serum ELISA was informative in potential triaging of patients with elevated levels of STn. However, it was not sensitive enough to add value to existing CA-125 levels for a diagnostic. While the ELISA identified non-serous ovarian tumors with low CA-125 levels, the sample numbers were too small to provide any confidence the STn ELISA would meaningfully add to CA-125 for diagnosis.

Conclusions

Our preclinical data support the concept that an anti-STn-ADC may be a viable option for treating patients with elevated STn levels. Moreover, our STn-based ELISA could complement IHC in identifying patients with whom an anti-STn-based strategy might be more effective.
The management of heart failure cardiogenic shock: an international RAND appropriateness panel
Authors: Williams Stefan , Kalakoutas Antonis , Olusanya Segun , Schrage Benedict , Tavazzi Guido , Carnicelli Anthony P. , Montero Santiago , Vandenbriele Christophe , Luk Adriana , Lim Hoong Sern , Bhagra Sai , Ott Sascha C. , Farrero Marta , Samsky Marc D. , Kennedy Jamie L. W. , Sen Sounok , Agrawal Richa , Rampersad Penelope , Coniglio Amanda , Pappalardo Federico , Barnett Christopher , Proudfoot Alastair G.
Published: April 2024

Background

Observational data suggest that the subset of patients with heart failure related CS (HF-CS) now predominate critical care admissions for CS. There are no dedicated HF-CS randomised control trials completed to date which reliably inform clinical practice or clinical guidelines. We sought to identify aspects of HF-CS care where both consensus and uncertainty may exist to guide clinical practice and future clinical trial design, with a specific focus on HF-CS due to acute decompensated chronic HF.

Methods

A 16-person multi-disciplinary panel comprising of international experts was assembled. A modified RAND/University of California, Los Angeles, appropriateness methodology was used. A survey comprising of 34 statements was completed. Participants anonymously rated the appropriateness of each statement on a scale of 1 to 9 (1–3 as inappropriate, 4–6 as uncertain and as 7–9 appropriate).

Results

Of the 34 statements, 20 were rated as appropriate and 14 were rated as inappropriate. Uncertainty existed across all three domains: the initial assessment and management of HF-CS; escalation to temporary Mechanical Circulatory Support (tMCS); and weaning from tMCS in HF-CS. Significant disagreement between experts (deemed present when the disagreement index exceeded 1) was only identified when deliberating the utility of thoracic ultrasound in the immediate management of HF-CS.

Conclusion

This study has highlighted several areas of practice where large-scale prospective registries and clinical trials in the HF-CS population are urgently needed to reliably inform clinical practice and the synthesis of future societal HF-CS guidelines.
Facial appearance associates with longitudinal multi-organ failure: an ICU cohort study
Authors: Cox Eline G. M. , van Bussel Bas C. T. , Campillo Llamazares Nerea , Sels Jan-Willem E. M. , Onrust Marisa , van der Horst Iwan C. C. , Koeze Jacqueline ,   SICS Study Group, Koster Geert , Koeze Jacqueline , Wiersema Renske , Keus Frederik , van der Horst Iwan C. C. , Dieperink Willem , Onrust Marisa ,   Simple Intensive Care Studies (SOCCS) student team, van der Veen Nynke , Irk Alexander , Roelofs Arlinde , Tijsma Leonie , Cox Eline , Llamazares Nerea Campillo , Holzhauer Lesley
Published: April 2024

Background

Facial appearance, whether consciously or subconsciously assessed, may affect clinical assessment and treatment strategies in the Intensive Care Unit (ICU). Nevertheless, the association between objective clinical measurement of facial appearance and multi-organ failure is currently unknown. The objective of this study was to examine whether facial appearance at admission is associated with longitudinal evaluation of multi-organ failure.

Methods

This was a sub-study of the Simple Intensive Care Studies-II, a prospective observational cohort study. All adult patients acutely admitted to the ICU between March 26, 2019, and July 10, 2019, were included. Facial appearance was assessed within three hours of ICU admission using predefined pictograms. The SOFA score was serially measured each day for the first seven days after ICU admission. The association between the extent of eye-opening and facial skin colour with longitudinal Sequential Organ Failure Assessment (SOFA) scores was investigated using generalized estimation equations.

Results

SOFA scores were measured in 228 patients. Facial appearance scored by the extent of eye-opening was associated with a higher SOFA score at admission and follow-up (unadjusted 0.7 points per step (95%CI 0.5 to 0.9)). There was no association between facial skin colour and a worse SOFA score over time. However, patients with half-open or closed eyes along with flushed skin had a lower SOFA score than patients with a pale or normal facial skin colour (P-interaction < 0.1).

Conclusions

The scoring of patients’ facial cues, primarily the extent of eye-opening and facial colour, provided valuable insights into the disease state and progression of the disease of critically ill patients. The utilization of advanced monitoring techniques that incorporate facial appearance holds promise for enhancing future intensive care support.
Glioblastoma-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts
Authors: Yabo Yahaya A. , Moreno-Sanchez Pilar M. , Pires-Afonso Yolanda , Kaoma Tony , Nosirov Bakhtiyor , Scafidi Andrea , Ermini Luca , Lipsa Anuja , Oudin Anaïs , Kyriakis Dimitrios , Grzyb Kamil , Poovathingal Suresh K. , Poli Aurélie , Muller Arnaud , Toth Reka , Klink Barbara , Berchem Guy , Berthold Christophe , Hertel Frank , Mittelbronn Michel , Heiland Dieter H. , Skupin Alexander , Nazarov Petr V. , Niclou Simone P. , Michelucci Alessandro , Golebiewska Anna
Published: April 2024

Background

A major contributing factor to glioblastoma (GBM) development and progression is its ability to evade the immune system by creating an immune-suppressive environment, where GBM-associated myeloid cells, including resident microglia and peripheral monocyte-derived macrophages, play critical pro-tumoral roles. However, it is unclear whether recruited myeloid cells are phenotypically and functionally identical in GBM patients and whether this heterogeneity is recapitulated in patient-derived orthotopic xenografts (PDOXs). A thorough understanding of the GBM ecosystem and its recapitulation in preclinical models is currently missing, leading to inaccurate results and failures of clinical trials.

Methods

Here, we report systematic characterization of the tumor microenvironment (TME) in GBM PDOXs and patient tumors at the single-cell and spatial levels. We applied single-cell RNA sequencing, spatial transcriptomics, multicolor flow cytometry, immunohistochemistry, and functional studies to examine the heterogeneous TME instructed by GBM cells. GBM PDOXs representing different tumor phenotypes were compared to glioma mouse GL261 syngeneic model and patient tumors.

Results

We show that GBM tumor cells reciprocally interact with host cells to create a GBM patient-specific TME in PDOXs. We detected the most prominent transcriptomic adaptations in myeloid cells, with brain-resident microglia representing the main population in the cellular tumor, while peripheral-derived myeloid cells infiltrated the brain at sites of blood–brain barrier disruption. More specifically, we show that GBM-educated microglia undergo transition to diverse phenotypic states across distinct GBM landscapes and tumor niches. GBM-educated microglia subsets display phagocytic and dendritic cell-like gene expression programs. Additionally, we found novel microglial states expressing cell cycle programs, astrocytic or endothelial markers. Lastly, we show that temozolomide treatment leads to transcriptomic plasticity and altered crosstalk between GBM tumor cells and adjacent TME components.

Conclusions

Our data provide novel insights into the phenotypic adaptation of the heterogeneous TME instructed by GBM tumors. We show the key role of microglial phenotypic states in supporting GBM tumor growth and response to treatment. Our data place PDOXs as relevant models to assess the functionality of the TME and changes in the GBM ecosystem upon treatment.

Graphical Abstract
Manufacturing, quality control, and GLP-grade preclinical study of nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles
Authors: Wang Jing , Chen Zhong-jin , Zhang Ze-yi , Shen Mei-ping , Zhao Bo , Zhang Wei , Zhang Ye , Lei Ji-gang , Ren Cheng-jie , Chang Jing , Xu Cui-li , Li Meng , Pi Yang-yang , Lu Tian-lun , Dai Cheng-xiang , Li Su-ke , Li Ping
Published: April 2024

Background

Human adipose stromal cells-derived extracellular vesicles (haMSC-EVs) have been shown to alleviate inflammation in acute lung injury (ALI) animal models. However, there are few systemic studies on clinical-grade haMSC-EVs. Our study aimed to investigate the manufacturing, quality control (QC) and preclinical safety of clinical-grade haMSC-EVs.

Methods

haMSC-EVs were isolated from the conditioned medium of human adipose MSCs incubated in 2D containers. Purification was performed by PEG precipitation and differential centrifugation. Characterizations were conducted by nanoparticle tracking analysis, transmission electron microscopy (TEM), Western blotting, nanoflow cytometry analysis, and the TNF-α inhibition ratio of macrophage [after stimulated by lipopolysaccharide (LPS)]. RNA-seq and proteomic analysis with liquid chromatography tandem mass spectrometry (LC–MS/MS) were used to inspect the lot-to-lot consistency of the EV products. Repeated toxicity was evaluated in rats after administration using trace liquid endotracheal nebulizers for 28 days, and respiratory toxicity was evaluated 24 h after the first administration. In vivo therapeutic effects were assessed in an LPS-induced ALI/ acute respiratory distress syndrome (ARDS) rat model.

Results

The quality criteria have been standardized. In a stability study, haMSC-EVs were found to remain stable after 6 months of storage at − 80°C, 3 months at − 20 °C, and 6 h at room temperature. The microRNA profile and proteome of haMSC-EVs demonstrated suitable lot-to-lot consistency, further suggesting the stability of the production processes. Intratracheally administered 1.5 × 108 particles/rat/day for four weeks elicited no significant toxicity in rats. In LPS-induced ALI/ARDS model rats, intratracheally administered haMSC-EVs alleviated lung injury, possibly by reducing the serum level of inflammatory factors.

Conclusion

haMSC-EVs, as an off-shelf drug, have suitable stability and lot-to-lot consistency. Intratracheally administered haMSC-EVs demonstrated excellent safety at the tested dosages in systematic preclinical toxicity studies. Intratracheally administered haMSC-EVs improved the lung function and exerted anti-inflammatory effects on LPS-induced ALI/ARDS model rats.
Knowledge and attitude of healthcare prescribers and pharmacists toward antimicrobial stewardship program and the barriers for its implementation
Authors: Jarab Anan S. , AL-Alawneh Tasneem O. , Alshogran Osama Y. , Heshmeh Shrouq Abu , Mukattash Tareq L. , Naser Yara A. , Alefishat Eman
Published: April 2024

Background

Antimicrobial stewardship (ASP) is considered a key prevention strategy in addressing the worldwide concern of accelerating antimicrobial resistance. Limited research is available regarding healthcare providers’ knowledge and attitude toward antimicrobial stewardship and the barriers for its implementation.

Methods

The present cross-sectional study was conducted on pharmacists and healthcare prescribers (HCPs) in different hospital sites across Jordan. A validated survey was used to evaluate HCPs and pharmacists’ knowledge, and attitudes towards ASP and the barriers for its implementation. Logistic and linear regression were conducted to identify the factors associated with knowledge and attitude toward ASP, respectively.

Results

A total of 603 participants, 69 (11.4%) pharmacists and 534 (88.6%) HCPs completed the study questionnaire, with a response rate of 80.4%. The overall mean knowledge about ASP was 7.16 out of 10, ranging from 0 to 10 (SD 2.22). Being a pharmacist and increased awareness/familiarity about ASP were associated with improved ASP knowledge. The overall average attitude score was = 3.8 ± 0.49 (range: 1.8–4.8). Results revealed that being a pharmacist and improved knowledge were associated with improved attitude toward ASP. Lack of specialized staff with expertise in ASP and lack of access to education and training programs were the major barriers hinder ASP implementation.

Conclusion

Despite the reasonable knowledge and the positive attitude toward the ASP, several barriers were reported, particularly by the pharmacists. Therefore, promoting the presence of adequately skilled healthcare personnel, creating easily accessible online courses, and establishing a comprehensive database of ASP resources are all suggested approaches to improve the application of ASP in healthcare settings.