bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying STRN3-RARA as a new fusion gene for acute promyelocytic leukemia
Authors: Zhang Qi , Li He , Chen Xuelan , Gu Fan , Zhang Lanxin , Zhang Lu , Chen Tong , Chen Qiang , Meng Wentong , Wu Yu , Chang Hong , Liu Ting , Chen Chong , Ma Hongbing , Liu Yu
Published: August 2023

Here we report a new fusion gene, STRN3-RARA, in acute promyelocytic leukemia (APL). It cooperates with UTX deficiency to drive full-blown APL in mice. Although STRN3-RARA leukemia quickly relapses after all-trans retinoic acid treatment, it can be restrained by cepharanthine.
The oxylipin analog CS585 prevents platelet activation and thrombosis through activation of the prostacyclin receptor
Authors: Stanger Livia , Yamaguchi Adriana , Yalavarthi Pooja , Lambert Sylviane , Gilmore Devin , Rickenberg Andrew , Luke Catherine , Kumar Kiran , Obi Andrea T. , White Andrew , Bergh Niklas , Dahlöf Björn , Holinstat Michael
Published: August 2023

Cardiovascular disease remains the primary cause of morbidity and mortality globally. Platelet activation is critical for maintaining hemostasis and preventing the leakage of blood cells from the vessel. There has been a paucity in the development of new drugs to target platelet reactivity. Recently, the oxylipin 12(S)-hydroxy-eicosatrienoic acid (12-HETrE), which is produced in platelets, was shown to limit platelet reactivity by activating the prostacyclin receptor. Here, we demonstrated the synthesis of a novel analog of 12-HETrE, known as CS585. Human blood and mouse models of hemostasis and thrombosis were assessed for the ability of CS585 to attenuate platelet activation and thrombosis without increasing the risk of bleeding. Human platelet activation was assessed using aggregometry, flow cytometry, western blot analysis, total thrombus formation analysis system, microfluidic perfusion chamber, and thromboelastography. Hemostasis, thrombosis, and bleeding assays were performed in mice. CS585 was shown to potently target the prostacyclin receptor on the human platelet, resulting in a highly selective and effective mechanism for the prevention of platelet activation. Furthermore, CS585 was shown to inhibit platelet function in human whole blood ex vivo, prevent thrombosis in both small and large vessels in mouse models, and exhibit long-lasting prevention of clot formation. Finally, CS585 was not observed to perturb coagulation or increase the risk of bleeding in the mouse model. Hence, CS585 represents a new validated target for the treatment of thrombotic diseases without the risk of bleeding or off-target activation observed with other prostaglandin receptor agonists.
Treatment strategy for acquired pure red cell aplasia: a systematic review and meta-analysis
Authors: Lobbes Hervé , Lega Jean-Christophe , Le Guenno Guillaume , Ruivard Marc , Mainbourg Sabine
Published: August 2023

The treatment of autoimmune acquired pure red cell aplasia (aPRCA) is challenging. Guidelines are based on expert recommendations in the absence of controlled trials. We assessed the efficacy of the main treatment strategy through a systematic review and meta-analysis using MEDLINE, EMBASE, and the Cochrane Library up to September 2022. The overall response rate (ORR) was pooled using random-effects models. In total, 24 observational studies (19 retrospective, median follow-up of 48 months) encompassing 753 patients (49% male) were included. Primary aPRCA represented 57% of the cases. The risk of bias was moderate to high using the ROBINS-I tool. Substantial heterogeneity (I2 > 50%) was retrieved. Corticosteroids as monotherapy as first-line treatment (186 patients, 13 studies) provided an ORR of 47% (95% confidence interval [CI], 34-60). Cyclosporine A was the most frequently used immunosuppressant agent (384 patients, 18 studies), providing an ORR of 74% (95% CI, 66-82) with a similar ORR in first- (73%) and second-line (76%) treatment and when cyclosporin was used as monotherapy (83%) or with corticosteroids (77%). A total of 112 patients (10 studies) received cyclophosphamide, with an ORR of 49% (95% CI, 35-64), which was higher when cyclophosphamide was combined with corticosteroids (48%) and used in second-line treatment (58%) than in monotherapy (31%), and in first-line treatment (44%). Sirolimus use was reported only after cyclosporine A failure and provided an ORR of 87% (95% CI, 68-100; 64 patients, 3 studies). Substantial uncertainty remains regarding the best treatment strategy in the absence of high-quality evidence. This study was registered on the PROPERO database as #CRD42022360452.
Elevated galectin-3 levels detected in women with hyperglycemia during early and mid-pregnancy antagonizes high glucose − induced trophoblast cells apoptosis via galectin-3/foxc1 pathway
Authors: Deng Yu , Jin Hongyan , Ning Jie , Cui Dong , Zhang Muqiu , Yang Huixia
Published: August 2023

Objective

This study was to evaluate plasma galectin-3 levels from early pregnancy to delivery and explore the effects of galectin-3 on the function of trophoblast cells under high glucose exposure.

Methods

The plasma galectin-3 levels were quantified by enzyme-linked immunosorbent assay (ELISA) in the China National Birth Cohort (CNBC) at Peking University First Hospital, and the underlying signaling pathway was identified by protein–protein interaction (PPI) analysis, gene set enrichment analysis (GSEA), quantitative PCR (qPCR), western blotting, small interfering RNA (siRNA) transfections, and flow cytometry.

Results

Significantly higher galectin-3 levels were found in patients with gestational diabetes mellitus (GDM group; n = 77) during the first and second trimesters than that in healthy pregnant women (HP group; n = 113) (P < 0.05). No significant differences in plasma galectin-3 levels were detected between GDM and HP groups in maternal third-trimester blood and cord blood. PPI analysis suggested potential interactions between galectin-3 and foxc1. The findings of GSEA showed that galectin-3 was involved in the cytochrome P450-related and complement-related pathways, and foxc1 was associated with type I diabetes mellitus. Additionally, high glucose (25 mM) significantly increased the expression levels of galectin-3 and foxc1 and induced apoptosis in HTR-8/SVneo cells. Further in vitro experiments showed that galectin-3/foxc1 pathway could protect HTR-8/SVneo cells against high glucose − induced apoptosis.

Conclusion

Future studies were required to validate whether plasma galectin-3 might become a potential biomarker for hyperglycemia during pregnancy. Elevated galectin-3 levels might be a vital protective mechanism among those exposed to hyperglycemia during pregnancy.

Graphical Abstract
CRISPR/Cas13d targeting GZMA in PARs pathway regulates the function of osteoclasts in chronic apical periodontitis
Authors: Jia Tingting , Yuan Fang , Tao Jingqiao , Wang Gang , Zhang Xianhua , Zhang Bin , Li Hongbo
Published: August 2023

Chronic apical periodontitis is a prevalent oral disease characterized by bone loss, and its underlying mechanisms remain unclear. This study aimed to investigate the role and mechanism of the serine protease GZMA in osteoclasts during chronic apical periodontitis. To address this, we employed crRNA/Cas13d to inhibit GZMA expression and examined its impact on osteoclast behavior. Our findings revealed that GZMA plays a significant role in promoting osteoclast cell proliferation while inhibiting cell apoptosis. Additionally, the inhibition of GZMA led to a notable increase in miR-25-3p expression, which, in turn, downregulated the expression of TGF-β. Consequently, the reduction in TGF-β expression led to a decrease in PAR1 expression within the PARs pathway. These results suggest that GZMA might serve as a promising therapeutic target for the treatment of chronic apical periodontitis. Furthermore, our study highlights the potential of targeting GZMA using crRNA/Cas13d as a valuable approach for future therapeutic interventions.
Predicting weighted unobserved nodes in a regulatory network using answer set programming
Authors: Le Bars Sophie , Bolteau Mathieu , Bourdon Jérémie , Guziolowski Carito
Published: August 2023

Background

The impact of a perturbation, over-expression, or repression of a key node on an organism, can be modelled based on a regulatory and/or metabolic network. Integration of these two networks could improve our global understanding of biological mechanisms triggered by a perturbation. This study focuses on improving the modelling of the regulatory network to facilitate a possible integration with the metabolic network. Previously proposed methods that study this problem fail to deal with a real-size regulatory network, computing predictions sensitive to perturbation and quantifying the predicted species behaviour more finely.

Results

To address previously mentioned limitations, we develop a new method based on Answer Set Programming, MajS. It takes a regulatory network and a discrete partial set of observations as input. MajS tests the consistency between the input data, proposes minimal repairs on the network to establish consistency, and finally computes weighted and signed predictions over the network species. We tested MajS by comparing the HIF-1 signalling pathway with two gene-expression datasets. Our results show that MajS can predict 100% of unobserved species. When comparing MajS with two similar (discrete and quantitative) tools, we observed that compared with the discrete tool, MajS proposes a better coverage of the unobserved species, is more sensitive to system perturbations, and proposes predictions closer to real data. Compared to the quantitative tool, MajS provides more refined discrete predictions that agree with the dynamic proposed by the quantitative tool.

Conclusions

MajS is a new method to test the consistency between a regulatory network and a dataset that provides computational predictions on unobserved network species. It provides fine-grained discrete predictions by outputting the weight of the predicted sign as a piece of additional information. MajS’ output, thanks to its weight, could easily be integrated with metabolic network modelling.
Effect of intraoperative muscle relaxation reversal on the success rate of motor evoked potential recording in patients undergoing spinal surgery: a randomized controlled trial
Authors: Jian Minyu , Liu Haiyang , Liang Fa , Ma Bo , Wang Lianjie , Zhou Yang , Qiao Hui , Han Ruquan , Wang Chengwei
Published: August 2023

Background

Partial neuromuscular blockade (NMB) has been applied for some surgeries to reduce bleeding and prevent patient movement for spinal surgery. Sugammadex selectively binds to rocuronium in the plasma and consequently lowers the rocuronium concentration at the neuromuscular junction. In this study, we aimed to observe whether the success rate of transcranial motor-evoked potential (TceMEP) can be increased by sugammadex compared with partial NMB during spinal surgery.

Methods

Patients who underwent elective spinal surgery with TceMEP monitoring were randomly assigned to the sugammadex group and control group. Rocuronium was continuously infused to maintain the train of four counts (TOFc) = 2. The sugammadex group discontinued rocuronium infusion at the time of TceMEP monitoring and was infused with 2 mg/kg sugammadex; the control group was infused with the same dose of saline.

Results

A total of 171 patients were included. The success rate of TceMEP monitoring in the sugammadex group was significantly higher than that in the control group. TceMEP amplitudes were greater in the sugammadex group than in the control group at 5 min, 10 min, and 20 min after the start of motor-evoked potential monitoring. The latencies of upper extremity TceMEPs monitoring showed no difference between groups. TOF ratios were greater in the sugammadex group at 5 min, 10 min, and 20 min after the start of motor-evoked potential monitoring. There were no adverse effects caused by sugammadex.

Conclusions

Sugammadex can improve the success rate of motor-evoked potential monitoring compared with moderate neuromuscular blockade induced by continuous infusion of rocuronium in spinal surgery.

Trial registration

The study was registered on clinicaltrials.gov.cn on 29/10/2020 (trial registration number: NCT04608682).
Barriers and facilitators of older adults for professional mental health help-seeking: a systematic review
Authors: Elshaikh Usra , Sheik Rayan , Saeed Raghad Khaled Mohammad , Chivese Tawanda , Alsayed Hassan Diana
Published: August 2023

Background

Older adults are at an increased risk for mental health issues, yet they are less likely to seek professional help. This systematic review aims to identify and summarize literature on the barriers and facilitators that older adults face when seeking professional mental health help.

Methods

A comprehensive literature search was conducted using multiple databases including PubMed-Medline, EMBASE, ProQuest central, CINAHL and Scopus to identify relevant studies published between 2010 and 2021 that focused on barriers and/or facilitators to seeking help for depression, anxiety, and psychological distress among older adults aged 65 years or older. Studies’ risk of bias was assessed using the Newcastle–Ottawa Scale and results of studies were synthesized guided by the methodological framework of Rodgers and colleagues.

Results

A total of eight cross-sectional studies, from Australia, United States, Mexico, Netherlands, and Malaysia met the inclusion criteria for this review. Included studies reported that the majority of their participants had anxiety or depression, yet they exhibited a preference for informal mental health help over professional help. Stigma, negative beliefs about mental health professional services, and cost were the most reported barriers. Main reported facilitators were prior positive experience with mental health services and high socioeconomic status.

Conclusion

Older adults are in need of interventions normalizing mental health help seeking and ensuring these services are accessible in terms of costs. This should be the focus of policy makers, healthcare providers, and public health practitioners working with older adults.

Protocol registration

PROSPERO 2021 CRD42021238853.
Prognostic models for estimating severity of disease and predicting 30-day mortality of Hypervirulent Klebsiella pneumoniae infections: a bicentric retrospective study
Authors: Huang Jieen , Chen Yanzhu , Li Ming , Xie Shujin , Tong Huasheng , Guo Zhusheng , Chen Yi
Published: August 2023

Background

Hypervirulent Klebsiella pneumoniae (hvKP) is emerging globally and can cause various, severe infections in healthy individuals. However, the clinical manifestations of hvKP infections are nonspecific, and there is no gold standard for differentiating hvKP strains. Our objective was to develop prognostic models for estimating severity of disease and predicting 30-day all-cause mortality in patients with hvKP infections.

Methods

We enrolled 116 patients diagnosed with hvKP infections and obtained their demographic and clinical data. Taking septic shock and acute respiratory distress syndrome (ARDS) as the primary outcomes for disease severity and 30-day all-cause mortality as the primary outcome for clinical prognosis, we explored the influencing factors and constructed prognostic models.

Results

The results showed that increased Acute Physiologic and Chronic Health Evaluation (APACHE) II score [odds ratio (OR) = 1.146; 95% confidence interval (CI), 1.059–1.240], decreased albumin (ALB) level (OR = 0.867; 95% CI, 0.758–0.990), diabetes (OR = 9.591; 95% CI, 1.766–52.075) and high procalcitonin (PCT) level (OR = 1.051; 95%CI, 1.005–1.099) were independent risk factors for septic shock. And increased APACHE II score (OR = 1.254; 95% CI, 1.110–1.147), community-acquired pneumonia (CAP) (OR = 11.880; 95% CI, 2.524–55.923), and extrahepatic lesion involved (OR = 14.718; 95% CI, 1.005–215.502) were independent risk factors for ARDS. Prognostic models were constructed for disease severity with these independent risk factors, and the models were significantly correlated with continuous renal replacement therapy (CRRT) duration, vasopressor duration, mechanical ventilator duration and length of ICU stay. The 30-day all-cause mortality rate in our study was 28.4%. Younger age [hazard ratio (HR) = 0.947; 95% CI, 0.923–0.973)], increased APACHE II score (HR = 1.157; 95% CI, 1.110–1.207), and decreased ALB level (HR = 0.924; 95% CI, 0.869–0.983) were the independent risk factors for 30-day all-cause mortality. A prediction model for 30-day mortality was constructed, which had a good validation effect.

Conclusions

We developed validated models containing routine clinical parameters for estimating disease severity and predicting 30-day mortality in patients with hvKP infections and confirmed their calibration. The models may assist clinicians in assessing disease severity and estimating the 30-day mortality early.
Effects of reduced follicle-stimulating hormone dosage before human chorionic gonadotropin trigger on in vitro fertilization outcomes
Authors: Ou Zhanhui , Du Jing , Liu Nengqing , Li Jieliang , Lin Xiufeng
Published: August 2023

Objective

To determine whether a reduced dose of follicle-stimulating hormone (FSH) before human chorionic gonadotropin (hCG) trigger during ovarian stimulation can affect in vitro fertilization (IVF) outcomes.

Methods

This study included 347 patients with a normal ovarian response who received a reduced dose of FSH before hCG trigger for 2–3 days (Group A) and 671 patients who did not receive a reduced dose (Group B) from a university-affiliated IVF center between January 2021 and December 2022. The primary endpoint was estrogen (E2) and progesterone (P) levels on the day of hCG trigger, fresh embryo transfer cycles, laboratory outcomes, and clinical outcomes between the two groups.

Results

On the day of hCG trigger, Group A had significantly lower E2 and P levels than those in Group B (3454.95 ± 1708.14 pg/mL versus 3798.70 ± 1774.26 pg/mL, p = 0.003; and 1.23 ± 0.53 ng/mL versus 1.37 ± 0.59 ng/mL, p < 0.001, respectively). The proportion of patients with P levels ≥ 1.5 ng/mL was 22.48% in Group A compared to 34.58% in Group B (p < 0.001), while the proportion of patients with E2 ≥ 5000 pg/mL was 15.27% in Group A compared to 25.93% in Group B (p < 0.001). The fresh embryo-transfer cycle rate in Group A was higher than that in group B (54.47% and 32.64%, respectively; p < 0.001). Despite the reduction in FSH dosage, there were no significant differences between groups regarding the number of oocytes retrieved, total number of mature oocytes, normal fertilization rate, cleavage rate, Day 3 top-quality rate, implantation rate, pregnancy rate per cycle, and early pregnancy loss rate.

Conclusion

While a reduced dose of FSH prior to hCG trigger during ovarian stimulation did not significantly affect IVF outcomes, it was associated with lower E2 and P levels, resulting in fewer cycles with E2 ≥ 5000 pg/mL and P ≥ 1.5 ng/mL on the day of the hCG trigger.
A novel smoothed (SMO) point mutation in congenital tibial hemimelia: a case report
Authors: Yang Xiaodong , Pu Siyu , Xiang Bo , Tang Xueyang , Chen Jing
Published: August 2023

Background

Congenital tibial hemimelia (CTH [MIM: 275220]) is a rare congenital limb deficiency that manifests as a shortened, curved, dysplastic or absent tibia with polydactyly. In previous studies, mutations of a distant sonic hedgehog (SHH) cis-regulator (ZRS) and a Shh repressor (GLI3) were identified.

Case presentation

Here, we admitted a 20-month-old boy who manifested with right tibial deformity, varus foot, ankle dislocation, and ipsilateral preaxial polydactyly. After genetic sequencing and data analysis, the results revealed a 443 A > G mutation in the father and a 536 C > T mutation in the mother in exon 2 of the Smoothed (SMO) gene at 7q32.1, with the coexistence of both mutant alleles in the proband/patient.

Conclusions

Our report suggests that even though not previously reported, SMO mutations may be associated with limb anomalies such as tibial hemimelia via Hh signaling in humans and has implications for genetic counseling.
Using the Health Belief Model to assess COVID-19 perceptions and behaviours among a group of Egyptian adults: a cross-sectional study
Authors: Boulos Dina N. K. , Hassan Azza Mohammed
Published: August 2023

Background

It is crucial to study the public’s perceptions and behaviour during a pandemic as this will be the driving force for practicing recommended precautions. The current study aimed to identify perceptions of a group of Egyptian adults to COVID-19 using the Health Belief Model (HBM), to measure self-reported practice of preventive behaviours and to identify influencing factors.

Methods

Cross sectional study was used, including Egyptian adults aged 18 + years. A structured anonymous online questionnaire was used including: a demographic section, the modified MERS- CoV Health Belief Model scale after addition of questions related to COVID-19 and questions on preventive behaviours to COVID-19.

Results

Of the 532 study participants, 28.6% were males, age ranges (18 to 74 years). There was a statistically significant positive correlation between total practice score and all COVID-19 Health Belief Model constructs total scores except for perceived barriers score showing negative correlation (P value < 0.05). Linear regression analysis showed that older age, male gender and living inside Cairo were associated with lower practice score (P value < 0.01).

Conclusions

Increased perceived susceptibility, perceived benefits, cues to action and perceived self-efficacy scores were associated with higher practice score in the current study. Additionally, results revealed that social media and websites can play an important role in shaping risk perception in the community. Stressing risk perception and efficacy beliefs prevention message can drive people to practice preventive behaviors.
School health systems under strain: an example of COVID-19 experiences & burnout among school health staff in Pima County, Arizona
Authors: Wilson Amanda M. , Ravi Priyanka , Pargas Nicole T. , Gerald Lynn B. , Lowe Ashley A.
Published: August 2023

Background

School health staff lead and provide a variety of care for children in schools. As school districts have navigated the COVID-19 pandemic, school health staff have faced unprecedented challenges in protecting the health of students and school staff. Our objective was to qualitatively characterize these pandemic challenges and experiences of school health staff in Pima County, Arizona to identify gaps in school health staff support for improving future emergency preparedness.

Methods

We conducted two focus group discussions (FGDs) with 48 school health staff in Pima County, Arizona in two school districts using a discussion guide including ten open-ended questions. The FGDs were audio recorded and transcribed verbatim. We used the socioecological model (SEM) to organize the thematic analysis and generate codes and themes; data were analyzed using Atlas.ti software.

Findings

The pandemic has significantly challenged school health staff with new pandemic-related job tasks: managing isolation, vaccination, and developing/implementing new and evolving COVID-19 guidelines. School health staff also reported increased stress related to interactions with parents and school administration as well as frustrations with rapid changes to guidance from the health department and policy makers. A common issue was not having enough staff or resources to complete regular job responsibilities, such as providing care for students with non-COVID-19 related health issues.

Conclusions

Increased workload for school health staff resulted in physical burnout, mental distress, and disruption of core functions with long term implications for children’s health. These focus groups highlight the need for improved emergency preparedness in schools during pandemics or infectious disease outbreaks. These include basic infrastructure changes (e.g., personnel support from health departments for tasks such as contact tracing to enable school nurses to continue core functions), and increased funding to allow for hazard pay and more school health personnel during emergency situations. In addition, basic school health infrastructure is lacking, and we should include a licensed school health nurse in every school.
Work-related musculoskeletal disorders in vulnerable populations: what are the most common body parts affected?
Authors: Gotardelo Marcele Pereira Silvestre , Rodrigues Allana Lima Moreira , Quaresma Fernando Rodrigues Peixoto , Pontes-Silva André , Maciel Erika da Silva
Published: August 2023

Background

Studies investigating vulnerable populations have shown that work-related musculoskeletal disorders have a negative impact on quality of life. However, no study has examined the body regions commonly affected by work-related musculoskeletal disorders in vulnerable populations.

Objective

To describe the body regions commonly affected by work-related musculoskeletal disorders in vulnerable populations.

Methods

Cross-sectional study. We used the ABEP questionnaire, the World Health Organization Quality of Life, the Nordic Musculoskeletal Disorders Questionnaire, the Perceived Stress Scale, and a self-report questionnaire to determine morning-evening in human circadian rhythms (chronotype assessment). To reduce the possibility of information bias, we provided prior training in the use of the instruments and created an electronic database that was filled out in duplicate (in cases of disagreement, a third researcher was consulted). We tested the normality of the data using the Shapiro–Wilk test.

Results

The sample consisted of 132 participants, but there was a sample loss of 41.6% (final sample n = 77). We observed the predominance of those who worked from 6 to 8 h/day, rest of 1 h during the working day, from 1 to 10 years of service and only 1 employment relationship. Regarding the quality of life, we observed a worse result in the domain related to the environment, as well as a stress level of 15.43 (± 7.52) with a maximum of 30. Finally, we observed the presence of pain self-reported by the artisanal fishermen in several regions of the body, lumbar being the most mentioned.

Conclusion

The neck, shoulders, arms, elbows, forearms, wrists, back, lumbar spine, and lower limbs are the most common parts of the body affected by work-related musculoskeletal disorders in artisanal fishermen.
Comprehensive analysis on subchondral bone marrow lesions of human osteoarthritis by integrating bulk and single-cell transcriptomes
Authors: Zeng Muhui , Wang Xiaoshuai , Chen Tianyu , Ruan Guangfeng , Li Jia , Xue Song , Zhao Yang , Hu Zhiyang , Xie Ye , Fan Tianxiang , Chen Shibo , Li Yang , Wang Qianyi , Zhang Yue , Zhang Rongkai , Lin Lijun , Ding Changhai , Zhu Zhaohua
Published: August 2023

Objective

This study aims to demonstrate the cellular composition and underlying mechanisms in subchondral bone marrow lesions (BMLs) of knee osteoarthritis (OA).

Methods

BMLs were assessed by MRI Osteoarthritis Knee Score (MOAKS)≥2. Bulk RNA-sequencing (bulk-seq) and BML-specific differentially expressed genes (DEGs) analysis were performed among subchondral bone samples (including OA-BML=3, paired OA-NBML=3; non-OA=3). The hub genes of BMLs were identified by verifying in independent datasets and multiple bioinformatic analyses. To further estimate cell-type composition of subchondral bone, we utilized two newly developed deconvolution algorithms (MuSiC, MCP-counter) in transcriptomic datasets, based on signatures from open-accessed single-cell RNA sequencing (scRNA-seq). Finally, competing endogenous RNA (ceRNA) and transcription factor (TF) networks were constructed through multiple predictive databases, and validated by public non-coding RNA profiles.

Results

A total of 86 BML-specific DEGs (up 79, down 7) were identified. IL11 and VCAN were identified as core hub genes. The “has-miR-424-5p/lncRNA PVT1” was determined as crucial network, targeting IL11 and VCAN, respectively. More importantly, two deconvolution algorithms produced approximate estimations of cell-type composition, and the cluster of heterotopic-chondrocyte was discovered abundant in BMLs, and positively correlated with the expression of hub genes.

Conclusion

IL11 and VCAN were identified as the core hub genes of BMLs, and their molecular networks were determined as well. We profiled the characteristics of subchondral bone at single-cell level and determined that the heterotopic-chondrocyte was abundant in BMLs and was closely linked to IL11 and VCAN. Our study may provide new insights into the microenvironment and pathological molecular mechanism of BMLs, and could lead to novel therapeutic strategies.
Empowerment interventions designed for persons living with chronic disease - a systematic review and meta-analysis of the components and efficacy of format on patient-reported outcomes
Authors: Stepanian Natalie , Larsen Marie Hamilton , Mendelsohn Joshua B. , Mariussen Kari L. , Heggdal Kristin
Published: August 2023

Background

Empowerment approaches are essential for building the capacity of individuals with chronic disease to be in control of their health. Reviews of empowerment interventions have been focused on specific chronic diseases, thereby limiting the scope of findings. This study had three aims: 1) to describe the characteristics of empowerment interventions covering a broad range of chronic diseases, 2) to clarify consistency with the World Health Organization`s (WHO) definition of empowerment as a process composed of four fundamental components and 3) to summarize outcome measures and estimate the effects in group and individual intervention formats.

Methods

Systematic literature review and meta-analysis. CINAHL, Medline, Embase, PsycINFO, Web of Science, COCHRANE and Central Register of Controlled Trials were searched using Chronic Disease, NCD, Empowerment, as MeSH terms. Eligible randomized and quasi randomized controlled trials were included. Review Manager 5.4 was used to conduct the meta-analysis. Risk of bias was assessed with the Cochrane risk-of-bias tool (ROB 2).

Results

Thirty-nine articles representing 8,011 participants were included in the review. A majority (82%) of studies reported robust evidence for changes on study-defined outcome measures in favor of interventions. Intervention content was assessed against WHO’s four fundamental components of empowerment, showing that all studies incorporated one component, but none targeted all components. Components reflecting knowledge acquisition, patient engagement with their health care providers and facilitating environment were scarcely reported. Meta-analyses found evidence for positive effects of group-format interventions measuring empowerment, HbA1c, and self-efficacy. Effects on empowerment were also found in some individual-format interventions. High levels of heterogeneity and variability among the conceptual frameworks were identified.

Conclusion

Empowerment interventions in group-format were most efficient, however, considerable conceptual inconsistencies were identified. Future studies should consolidate conceptual understandings by using WHO’s empowerment framework to ensure that fundamental components of empowerment are explicitly included in intervention design. Furthermore, there is a need to clarify the role of empowerment through pathways that include patient activation, self- management, and clinical outcomes. This systematic review will inform the clinicians and researchers who aim to develop novel empowerment interventions to assist patients in the process of gaining control of their health.

Trial registration

PROSPERO: International Prospective register of systematic reviews ID=CRD42020178286.
Metabolic characteristics and pathogenesis of precocious puberty in girls: the role of perfluorinated compounds
Authors: Wu Jinxia , Chen Jing , Huang Rong , Zhu Hongwei , Che Lin , Lin Yanyan , Chang Yajie , Shen Guiping , Feng Jianghua
Published: August 2023

Background

Precocious puberty (PP) in girls is traditionally defined as the onset of breast development before the age of 8 years. The specific biomarkers of premature thelarche (PT) and central precocious puberty (CPP) girls are uncertain, and little is known about their metabolic characteristics driven by perfluorinated compounds (PFCs) and clinical phenotype. This study aimed to screen specific biomarkers of PT and CPP and elucidate their underlying pathogenesis. The relationships of clinical phenotype-serum PFCs-metabolic characteristics were also explored to reveal the relationship between PFCs and the occurrence and development of PT and CPP.

Methods

Nuclear magnetic resonance (NMR)-based cross-metabolomics strategy was performed on serum from 146 PP (including 30 CPP, 40 PT, and 76 unspecified PP) girls and 64 healthy girls (including 36 prepubertal and 28 adolescent). Specific biomarkers were screened by the uni- and multivariate statistical analyses. The relationships between serum PFCs and clinical phenotype were performed by correlation analysis and weighted gene co-expression network analysis to explore the link of clinical phenotype-PFCs-metabolic characteristics in PT and CPP.

Results

The disordered trend of pyruvate and butyrate metabolisms (metabolites mapped as formate, ethanol, and 3-hydroxybutyrate) were shared and kept almost consistent in PT and CPP. Eight and eleven specific biomarkers were screened for PT and CPP, respectively. The area under curve of specific biomarker combination was 0.721 in CPP vs. prepubertal, 0.972 in PT vs. prepubertal, 0.646 in CPP vs. prepubertal integrated adolescent, and 0.822 in PT vs. prepubertal integrated adolescent, respectively. Perfluoro-n-heptanoic acid and perfluoro-n-hexanoic acid were statistically different between PT and CPP. Estradiol and prolactin were significantly correlated with PFCs in CPP and PT. Clinical phenotypes and PFCs drive the metabolic characteristics and cause metabolic disturbances in CPP and PT.

Conclusions

The elevation of formate, ethanol, and 3-hydroxybutyrate may serve as the early diagnostic indicator for PP in girls. But the stratification of PP still needs to be further determined based on the specific biomarkers. Specific biomarkers of CPP and PT exhibited good sensitivity and can facilitate the classification diagnosis of CPP and PT. PFC exposure is associated with endocrine homeostasis imbalance. PFC exposure and/or endocrine disturbance directly or indirectly drive metabolic changes and form overall metabolic network perturbations in CPP and PT.
Lipid profiles in patients with juvenile idiopathic arthritis: a systematic literature review and meta-analysis
Authors: Zhao Wen-Jia , Deng Jiang-Hong , Li Cai-Feng
Published: August 2023

Objective

The purpose of this study was to comprehensively evaluate the lipid profiles in patients with juvenile idiopathic arthritis (JIA).

Methods

The literature and relevant reviews were searched for published clinical studies on the relationship between JIA and blood lipid levels. The Newcastle–Ottawa scale (NOS) was applied to evaluate the risk and methodological value of the included case‒control and cohort studies. Standardized mean differences (SMDs) and 95% confidence intervals were derived for all variables with adequate unprocessed data. This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines.

Results

In total, 16 studies were incorporated through screening. The analysis findings revealed that the levels of very low-density lipoprotein cholesterol [SMD=-0.411, 95% CI (-0.774~-0.048), P = 0.026], high-density lipoprotein cholesterol [SMD=-0.528, 95% CI (-0.976~-0.079), P = 0.021], and apolipoprotein A1 [SMD=-1.050, 95% CI (-1.452~-0.647), P = 0.000] in JIA patients were statistically lower than those observed in healthy controls. The level of low-density lipoprotein cholesterol [SMD = 0.202, 95% CI (0.003 ~ 0.400), P = 0.046] was significantly higher in JIA patients than in healthy controls. In JIA patients, body mass index [SMD=-0.189, 95% CI (-0.690 ~ 0.311), P = 0.459], high-density lipoprotein [SMD =-1.235, 95% CI (-2.845 ~ 0.374), P = 0.133), low-density lipoprotein [SMD = 0.616, 95% CI (-0.813 ~ 2.046), P = 0.398), triglycerides (SMD = 0.278, 95% CI (-0.182 ~ 0.738), P = 0.236], total cholesterol [SMD=-0.073, 95% CI (-0.438 ~ 0.293), P = 0.696] and apolipoprotein B levels [SMD = 0.226, 95% CI (-0.133 ~ 0.585), P = 0.217] were not significantly different from those in healthy controls.

Conclusions

The outcomes of this meta-analysis suggest that dyslipidemia is common in JIA patients compared to healthy controls. Patients with JIA have a significantly increased risk of atherosclerosis and cardiovascular disease later in life.
RNF173 suppresses RAF/MEK/ERK signaling to regulate invasion and metastasis via GRB2 ubiquitination in Hepatocellular Carcinoma
Authors: Zhou Jie , Tu Daoyuan , Peng Rui , Tang Yuhong , Deng Qiangwei , Su Bingbing , Wang Shunyi , Tang Hao , Jin Shengjie , Jiang Guoqing , Wang Qian , Jin Xin , Zhang Chi , Cao Jun , Bai Dousheng
Published: August 2023

Background

The role of the membrane-associated RING-CH (MARCH) family in carcinogenesis has been widely studied, but the member of this family, RNF173, has not yet been thoroughly explored in the context of hepatocellular carcinoma (HCC).

Methods

With the use of an HCC tissue microarray and IHC staining, we aim to determine the differential expression of RNF173 in HCC patients and its clinical significance. The biological role of RNF173 is investigated through in vitro and in vivo experiments. RNA sequencing, mass spectrometry, and immunoprecipitation are performed to uncover the underlying mechanism of RNF173's impact on the development of HCC.

Results

The mRNA and protein levels of RNF173 were significantly lower in HCC tissues than in normal tissues. HCC patients with low RNF173 expression had shorter overall survival and recurrence-free survival, and RNF173 was significantly correlated with tumor number, tumor capsule, tumor differentiation, and BCLC stage. In addition, in vitro and in vivo experiments showed that RNF173 downregulation exacerbated tumor progression, including migration, invasion, and proliferation. GRB2 is a key molecule in the RAF/MEK/ERK pathway. RNF173 inhibits the RAF/MEK/ERK signaling by ubiquitinating and degrading GRB2, thereby suppressing HCC cell proliferation, invasion and migration. Combining clinical samples, we found that HCC patients with high RNF173 and low GRB2 expression had the best prognosis.

Conclusion

RNF173 inhibits the invasion and metastasis of HCC by ubiquitinating and degrading GRB2, thereby suppressing the RAF/MEK/ERK signaling pathway. RNF173 is an independent risk factor for the survival and recurrence of HCC patients. RNF173 may serve as a novel prognostic molecule and potential therapeutic target for HCC.

Graphical Abstract

Graphical abstract Model of RNF173 on RAF/MEK/ERK signaling. RNF173 knockdown resulted in impaired ubiquitination and degradation of GRB2, leading to the activation of the RAF/MEK/ERK signaling pathway and promotion of invasion and metastasis in HCC cells.
Estimation of transpulmonary driving pressure during synchronized mechanical ventilation using a single lower assist maneuver (LAM) in rabbits: a comparison to measurements made with an esophageal balloon
Authors: Liu Ling , Li Hong-Liang , Lu Cong , Patel Purab , Wang Danqiong , Beck Jennifer , Sinderby Christer
Published: August 2023

Background

Mechanical ventilation is applied to unload the respiratory muscles, but knowledge about transpulmonary driving pressure (ΔPL) is important to minimize lung injury. We propose a method to estimate ΔPL during neurally synchronized assisted ventilation, with a simple intervention of lowering the assist for one breath (“lower assist maneuver”, LAM).

Methods

In 24 rabbits breathing spontaneously with imposed loads, titrations of increasing assist were performed, with two neurally synchronized modes: neurally adjusted ventilatory assist (NAVA) and neurally triggered pressure support (NPS). Two single LAM breaths (not sequentially, but independently) were performed at each level of assist by acutely setting the assist to zero cm H2O (NPS) or NAVA level 0 cm H2O/uV (NAVA) for one breath. NPS and NAVA titrations were followed by titrations in controlled-modes (volume control, VC and pressure control, PC), under neuro-muscular blockade. Breaths from the NAVA/NPS titrations were matched (for flow and volume) to VC or PC. Throughout all runs, we measured diaphragm electrical activity (Edi) and esophageal pressure (PES). We measured ΔPL during the spontaneous modes (PL_PES) and controlled mechanical ventilation (CMV) modes (PL_CMV) with the esophageal balloon. From the LAMs, we derived an estimation of ΔPL (“PL_LAM”) using a correction factor (ratio of volume during the LAM and volume during assist) and compared it to measured ΔPL during passive (VC or PC) and spontaneous breathing (NAVA or NPS). A requirement for the LAM was similar Edi to the assisted breath.

Results

All animals successfully underwent titrations and LAMs for NPS/NAVA. One thousand seven-hundred ninety-two (1792) breaths were matched to passive ventilation titrations (matched Vt, r = 0.99). PL_LAM demonstrated strong correlation with PL_CMV (r = 0.83), and PL_PES (r = 0.77). Bland–Altman analysis revealed little difference between the predicted PL_LAM and measured PL_CMV (Bias = 0.49 cm H2O and 1.96SD = 3.09 cm H2O). For PL_PES, the bias was 2.2 cm H2O and 1.96SD was 3.4 cm H2O. Analysis of Edi and PES at peak Edi showed progressively increasing uncoupling with increasing assist.

Conclusion

During synchronized mechanical ventilation, a LAM breath allows for estimations of transpulmonary driving pressure, without measuring PES, and follows a mathematical transfer function to describe respiratory muscle unloading during synchronized assist.
Discovery biomarker to optimize obeticholic acid treatment for non-alcoholic fatty liver disease
Authors: Lee Seung Min , Jun Dae Won , Yoon Eileen Laurel , Oh Ju Hee , Roh Yoon Jin , Lee Eun Jeoung , Shin Ji-Hee , Nam Young-Do , Kim Hyun Sung
Published: August 2023

The response rate to obeticholic acid (OCA), a potential therapeutic agent for non-alcoholic fatty liver disease, is limited. This study demonstrated that upregulation of the alternative bile acid synthesis pathway increases the OCA treatment response rate. The hepatic transcriptome and bile acid metabolite profile analyses revealed that the alternative bile acid synthesis pathway (Cyp7b1 and muricholic acid) in the OCA-responder group were upregulated compared with those in the OCA-non-responder group. Intestinal microbiome analysis also revealed that the abundances of Bacteroidaceae, Parabacteroides, and Bacteroides, which were positively correlated with the alternative bile acid synthesis pathway, were higher in the OCA-responder group than in the non-responder group. Pre-study hepatic mRNA levels of Cyp8b1 (classic pathway) were downregulated in the OCA-responder group. The OCA response rate increased up to 80% in cases with a hepatic Cyp7b1/Cyp8b1 ratio ≥ 5.0. Therefore, the OCA therapeutic response can be evaluated based on the Cyp7b1/Cyp8b1 ratio or the alternative/classic bile acid synthesis pathway activity.
Safety and efficacy of camrelizumab combined with radiotherapy as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma: a prospective single-arm phase II clinical trial protocol
Authors: Chen Maohui , Huang Yizhou , Zhang Shuliang , Zeng Taidui , Huang Guanglei , Chen Chun , Zheng Bin
Published: August 2023

Background

Neoadjuvant chemoradiotherapy followed by esophagectomy is the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC). However, approximately 30% of patients still develop distant metastases and have a high incidence of treatment-related adverse events. Immunotherapy, as a new modality for anti-cancer treatment, has shown promising clinical benefits for patients with ESCC. The synergistic effects of immunotherapy and radiotherapy make their combination promising as neoadjuvant treatment for locally advanced ESCC.

Methods

All participants who meet the inclusion criteria will be enrolled after signing the informed consent form. Patients with thoracic segment esophageal cancer with clinical stage T2–3 N0 M0 or T2–3 N + M0 will be included. A total of 25 patients are to be recruited for the study. Twelve patients will be recruited in phase I, with at least two achieving major pathological response (MPR) before entering phase II. They will be treated with radical surgery within 4–8 weeks after the completion of two cycles of neoadjuvant radiotherapy in combination with camrelizumab according to the study schedule. The primary endpoint is the major pathological remission rate of all per-protocol patients. The secondary endpoints are the R0 resection rate, pathological complete remission rate, and adverse events. The interim analysis will be conducted after 12 patients have been enrolled. The trials will be terminated when more than two treatment-related deaths occur or fewer than five patients have major pathological remission.

Discussion

We designed this prospective single-arm phase II clinical study to evaluate the combination of camrelizumab and standard radiotherapy as preoperative neoadjuvant therapy for patients with resectable ESCC as part of the quest for better treatment options for patients with locally advanced ESCC.

Trial registration

This trial protocol has been registered on the NIH Clinical Trials database (www.clinicaltrials.gov/, NCT05176002. Registered on 2022/01/04). The posted information will be updated as needed to reflect protocol amendments and study progress.
A cysteine proteinase inhibitor ALLN alleviates bleomycin-induced skin and lung fibrosis
Authors: Kasamatsu Hiroshi , Chino Takenao , Hasegawa Takumi , Utsunomiya Natsuko , Utsunomiya Akira , Yamada Masami , Oyama Noritaka , Hasegawa Minoru
Published: August 2023

Background

Systemic sclerosis (SSc) is a connective tissue disease that is characterized by fibrosis in the skin and internal organs, such as the lungs. Activated differentiation of progenitor cells, which are mainly resident fibroblasts, into myofibroblasts is considered a key mechanism underlying the overproduction of extracellular matrix and the resultant tissue fibrosis in SSc. Calpains are members of the Ca2+-dependent cysteine protease family, whose enzymatic activities participate in signal transduction and tissue remodeling, potentially contributing to fibrosis in various organs. However, the roles of calpain in the pathogenesis of SSc remain unknown. This study aimed to examine the anti-fibrotic properties of N-acetyl-Leu-Leu-norleucinal (ALLN), one of the cysteine proteinase inhibitors that primarily inhibit calpain, in vitro and in vivo, to optimally translate into the therapeutic utility in human SSc.

Methods

Normal human dermal and lung fibroblasts pretreated with ALLN were stimulated with recombinant transforming growth factor beta 1 (TGF-β1), followed by assessment of TGF-β1/Smad signaling and fibrogenic molecules.

Results

ALLN treatment significantly inhibited TGF-β1-induced phosphorylation and nuclear transport of Smad2/3 in skin and lung fibroblasts. TGF-β1-dependent increases in α-smooth muscle actin (αSMA), collagen type I, fibronectin 1, and some mesenchymal transcription markers were attenuated by ALLN. Moreover, our findings suggest that ALLN inhibits TGF-β1-induced mesenchymal transition in human lung epithelial cells. Consistent with these in vitro findings, administering ALLN (3 mg/kg/day) three times a week intraperitoneally remarkably suppressed the development of skin and lung fibrosis in a SSc mouse model induced by daily subcutaneous bleomycin injection. The number of skin- and lung-infiltrating CD3+ T cells decreased in ALLN-treated mice compared with that in control-treated mice. Phosphorylation of Smad3 and/or an increase in αSMA-positive myofibroblasts was significantly inhibited by ALLN treatment on the skin and lungs. However, no adverse effects were observed.

Conclusions

Our results prove that calpains can be a novel therapeutic target for skin and lung fibrosis in SSc, considering its inhibitor ALLN.