bluuebunny/crossref_metadata_2025 huggingface dataset:
Higher fasting triglyceride predicts higher risks of diabetes mortality in US adults
Authors: Wang Yutang
Published: December 2021

Background

It is unknown whether higher triglyceride results in higher mortality from diabetes, i.e., diabetes mortality. This study aimed to investigate the association of fasting triglyceride with diabetes mortality.

Methods

This study included 26,582 US adults from the National Health and Nutrition Examination Surveys from 1988 to 2014. Diabetes mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of triglyceride for diabetes mortality.

Results

Higher levels of fasting triglyceride were associated with higher levels of glucose, glycated hemoglobin, insulin, and homeostatic model assessment for insulin resistance at baseline. A 1-natural-log-unit increase in triglyceride (e.g., from 70 to 190 mg/dL) was associated with a 115% higher multivariate-adjusted risk of diabetes diagnosis (odds ratio, 2.15; 95% CI, 2.00–2.33). During 319,758 person-years of follow-up with a mean follow-up of 12.0 years, 582 diabetes deaths were documented. Compared with people with triglyceride in the lowest quintile, people with triglyceride in the highest quintile had an 85% higher risk of diabetes mortality (HR, 1.85; 95% CI, 1.25–2.73). A 1-natural-log-unit increase in triglyceride was associated with a 40% higher multivariate-adjusted risk of diabetes mortality. The positive association between triglyceride and diabetes mortality was also presented in sub-cohorts of participants with or without diabetes.

Conclusions

This study demonstrated that higher fasting triglyceride was associated with a higher diabetes mortality risk.
Autism spectrum disorders and atopic dermatitis: a new perspective from country-based prevalence data
Authors: Tonacci Alessandro , Pioggia Giovanni , Gangemi Sebastiano
Published: December 2021

Recently, a continuous growth for both neurodevelopmental and atopic diseases’ incidence was seen throughout the world. Notably, autism spectrum disorders (ASD) and atopic dermatitis (AD) attracted the attention of clinicians and scientists for their impact on the quality of life of patients, starting during childhood. Despite a number of hypotheses about common pathogenesis between the two disorders, uncertainty is still present, and data coming from various parts of the world are contradictory. Fortunately, works recently published have brought useful material for comparative analysis to the benefit of the scientific community, making large scale, country-based perspectives methodologically viable. In light of that, the present study took into account uniform data, available from country-based registries or related publications, dealing with the prevalence of the two conditions around the world, and tried to setup a simple correlation analysis between the two. According to such data, the growth of AD and ASD prevalence appear uncorrelated, leading to hypothesise that, if a common etiopathological pathway exists between the two conditions, they are likely to interact to each other due to a complex interplay of co-morbidities, genes and environmental players not enough explained by a simple correlation analysis. Such facts are worth investigation in future research.
Carbon nanotube biocompatibility in plants is determined by their surface chemistry
Authors: González-Grandío Eduardo , Demirer Gözde S. , Jackson Christopher T. , Yang Darwin , Ebert Sophia , Molawi Kian , Keller Harald , Landry Markita P.
Published: December 2021

Background

Agriculture faces significant global challenges including climate change and an increasing food demand due to a growing population. Addressing these challenges will require the adoption of transformative innovations into biotechnology practice, such as nanotechnology. Recently, nanomaterials have emerged as unmatched tools for their use as biosensors, or as biomolecule delivery vehicles. Despite their increasingly prolific use, plant-nanomaterial interactions remain poorly characterized, drawing into question the breadth of their utility and their broader environmental compatibility.

Results

Herein, we characterize the response of Arabidopsis thaliana to single walled carbon nanotube (SWNT) exposure with two different surface chemistries commonly used for biosensing and nucleic acid delivery: oligonucleotide adsorbed-pristine SWNTs, and polyethyleneimine-SWNTs loaded with plasmid DNA (PEI-SWNTs), both introduced by leaf infiltration. We observed that pristine SWNTs elicit a mild stress response almost undistinguishable from the infiltration process, indicating that these nanomaterials are well-tolerated by the plant. However, PEI-SWNTs induce a much larger transcriptional reprogramming that involves stress, immunity, and senescence responses. PEI-SWNT-induced transcriptional profile is very similar to that of mutant plants displaying a constitutive immune response or treated with stress-priming agrochemicals. We selected molecular markers from our transcriptomic analysis and identified PEI as the main cause of this adverse reaction. We show that PEI-SWNT response is concentration-dependent and, when persistent over time, leads to cell death. We probed a panel of PEI variant-functionalized SWNTs across two plant species and identified biocompatible SWNT surface functionalizations.

Conclusions

While SWNTs themselves are well tolerated by plants, SWNTs surface-functionalized with positively charged polymers become toxic and produce cell death. We use molecular markers to identify more biocompatible SWNT formulations. Our results highlight the importance of nanoparticle surface chemistry on their biocompatibility and will facilitate the use of functionalized nanomaterials for agricultural improvement.

Graphical Abstract
A cascade targeting strategy based on modified bacterial vesicles for enhancing cancer immunotherapy
Authors: Zhai Yuewen , Ma Yuying , Pang Bo , Zhang Jinnan , Li Ying , Rui Yalan , Xu Tian , Zhao Yu , Qian Zhiyu , Gu Yueqing , Li Siwen
Published: December 2021

Background

As an efficient tumor immunotherapy, PD-1 antibody has been gradually used in clinical tumor treatment, but the low response rate and excessive immune response limit its extensive application.

Results

Herein, a therapeutic regime for the reinvigoration and activation of the tumor immune microenvironment is introduced to improve the anti-tumor effect of the PD-1 antibody. To comprehensively improve the effect of the immunotherapy and reduce excessive immune response, a biomimetic cascade targeting nanosystem, siRNA@PLOV, which was fused by photothermal sensitive liposomes (PTSLs) and attenuatedSalmonellaouter membrane vesicles (OMVs), was administered in the tumor therapy for targeting of tumor tissues and T cells within tumor respectively. The fused PLOVs which not only retained the biological character of the OMVs, but also enhanced the drug loading ability. The results demonstrated that the immunogenicity of OMVs and photothermal effects can obviously increase the infiltration of T cells and the silencing of CD38 can effectively improve the T cell cytotoxicity, especially combining with PD-1 antibody.

Conclusions

Interesting, this study revealed that anti-PD-1 administration on the 5th day after siRNA@PLOV treatment had the best performance in killing tumors compared with other groups. In addition, this new therapeutic regime also presents a novel strategy for inducing “vaccine effects”, conclusively highlighting its potential in preventing tumor recurrence and improving prognosis.

Graphical Abstract
A redox-responsive dihydroartemisinin dimeric nanoprodrug for enhanced antitumor activity
Authors: Li Yawei , Pei Qing , Cui Baiji , Zhang Hongmei , Han Liu , Li Wenqing , Zhu Wenhe , Feng Xianmin , Xie Zhigang
Published: December 2021

Redox-responsive drug delivery system emerges as a hopeful platform for tumor treatment. Dihydroartemisinin (DHA) has been investigated as an innovative tumor therapeutic agent. Herein, a DHA dimeric prodrug bridged with disulfide bond as linker (DHA2-SS) has been designed and synthesized. The prepared prodrugs could self-assemble into nanoparticles (SS NPs) with high DHA content (> 90%) and robust stability. These SS NPs display sensitive redox responsive capability and can release DHA under the tumor heterogeneity microenvironment. SS NPs possess preferable antitumor therapeutic activity in contrast with free DHA. Moreover, the possible anti-cancer mechanism of SS NPs was investigated through RNA-seq analysis, bioinformatics and molecular biological method. SS NPs could induce apoptosis via mitochondrial apoptosis pathway, as well as glycolysis inhibition associate with the regulation of PI3K/AKT/HIF-1α signal path, which may offer an underlying therapeutic target for liver cancer. Our study highlights the potential of using redox responsive prodrug nanoparticles to treat cancer, meanwhile provides insights into the anti-cancer mechanism of DHA prodrug.

Graphical Abstract
Sternocleidomastoid flap for pedicled reconstruction in head & neck surgery- revisiting the anatomy and technique
Authors: Srivastava Apurva , Kumar Tarun , Pandey Shashi Kant , Shukla Ram Chandra , Pai Esha , Pandey Manoj
Published: December 2021

Background

Previous studies on sternocleidomastoid flaps, have defined the importance of preserving sternocleidomastoid (SCM) branch of superior thyroid artery (STA). This theory drew criticism, as this muscle is known to be a type II muscle, i.e., the muscle has one dominant pedicle (branches from the occipital artery at the superior pole) and smaller vascular pedicles entering the belly of muscle (branches from STA and thyrocervical trunk) at the middle and lower pole respectively. It was unlikely for the SCM branch of STA to supply the upper and lower thirds of the muscle. We undertook a cadaveric angiographic study to investigate distribution of STA supply to SCM muscle.

Methods

It is a cross-sectional descriptive study on 10 cadaveric SCM muscles along with ipsilateral STA which were evaluated with angiography using diatrizoate (urograffin) dye. Radiographic films were interpreted looking at the opacification of the muscle. Results were analyzed using frequency distribution and percentage.

Results

Out of ten specimens, near complete opacification was observed in eight SCM muscle specimens. While one showed poor uptake in the lower third of the muscle, the other showed poor uptake in the upper third segment of muscle.

Conclusion

Based on the above findings we suggest to further investigate sternocleidomastoid muscle as a type III flap, as the STA branch also supplies the whole muscle along with previously described pedicle from occipital artery. However, this needs to be further corroborated intra-operatively using scanning laser doppler. This also explains better survival rates of superior thyroid artery based sternomastoid flaps.
Effectiveness of a large-scale, sustained and comprehensive community health worker program in improving population health: the experience of an urban health district in South Africa
Authors: Thomas L. S. , Buch E. , Pillay Y. , Jordaan J.
Published: December 2021

Introduction

South Africa is an upper middle-income country with wide wealth inequality. It faces a quadruple burden of disease and poor health outcomes, with access to appropriate and adequate health care a challenge for millions of South Africans. The introduction of large-scale, comprehensive community health worker (CHW) programs in the country, within the context of implementing universal health coverage, was anticipated to improve population health outcomes. However, there is inadequate local (or global) evidence on whether such programs are effective, especially in urban settings.

Methods

This study is part of a multi-method, quasi-experimental intervention study measuring effectiveness of a large-scale CHW program in a health district in an urban province of South Africa, where CHWs now support approximately one million people in 280,000 households. Using interviewer administered questionnaires, a 2019 cross-sectional survey of 417 vulnerable households with long-term CHW support (intervention households) are compared to 417 households with no CHW support (control households). Households were selected from similar vulnerable areas from all sub-levels of the Ekurhuleni health district.

Results

The 417 intervention and control households each had good health knowledge. Compared to controls, intervention households with long-term comprehensive CHW support were more likely to access early care, get diagnosed for a chronic condition, be put on treatment and be well controlled on chronic treatment. They were also more likely to receive a social grant, and have a birth certificate or identity document. The differences were statistically significant for social support, health seeking behavior, and health outcomes for maternal, child health and chronic care.

Conclusion

A large-scale and sustained comprehensive CHW program in an urban setting improved access to social support, chronic and minor acute health services at household and population level through better health-seeking behavior and adherence to treatment. Direct evidence from households illustrated that such community health worker programs are therefore effective and should be part of health systems in low- and middle-income countries.
Health workforce strategies in response to major health events: a rapid scoping review with lessons learned for the response to the COVID-19 pandemic
Authors: Coates Alison , Fuad Asli-Oubah , Hodgson Amanda , Bourgeault Ivy Lynn
Published: December 2021

Background

The early weeks of the COVID-19 pandemic brought multiple concurrent threats—high patient volume and acuity and, simultaneously, increased risk to health workers. Healthcare managers and decision-makers needed to identify strategies to mitigate these adverse conditions. This paper reports on the health workforce strategies implemented in relation to past large-scale emergencies (including natural disasters, extreme weather events, and infectious disease outbreaks).

Methods

We conducted a rapid scoping review of health workforce responses to natural disasters, extreme weather events, and infectious disease outbreaks reported in the literature between January 2000 and April 2020. The 3582 individual results were screened to include articles which described surge responses to past emergencies for which an evaluative component was included in the report. A total of 37 articles were included in our analysis.

Results

The reviewed literature describes challenges related to increased demand for health services and a simultaneous decrease in the availability of the workforce. Many articles also described impacts on infrastructure that hindered emergency response. These challenges aligned well with those faced during the early days of the COVID-19 pandemic. In the published literature, the workforce strategies that were described aimed either to increase the numbers of health workers in a given area, to increase the flexibility of the health workforce to meet needs in new ways, or to support and sustain health workers in practice. Workforce responses addressed all types and cadres of health workers and were executed in a wide range of settings. We additionally report on the barriers and facilitators of workforce strategies reported in the literature reviewed. The strategies that were reported in the literature aligned closely with our COVID-specific conceptual framework of workforce capacity levers, suggesting that our framework may have heuristic value across many types of health disasters.

Conclusions

This research highlights a key deficiency with the existing literature on workforce responses to emergencies: most papers lack substantive evaluation of the strategies implemented. Future research on health workforce capacity interventions should include robust evaluation of impact and effectiveness.
Engaging citizens in the development of a health system performance assessment framework: a case study in Ireland
Authors: Brito Fernandes Óscar , Barbazza Erica , Ivanković Damir , Jansen Tessa , Klazinga Niek S. , Kringos Dionne S.
Published: December 2021

Background

The launch in 2017 of the Irish 10-year reform programme Sláintecare represents a key commitment in the future of the health system. An important component of the programme was the development of a health system performance assessment (HSPA) framework. In 2019, the Department of Health of Ireland (DoH) and Health Service Executive (HSE) commissioned the technical support of researchers to develop an outcome-oriented HSPA framework which should reflect the shared priorities of multiple stakeholders, including citizens. This study describes the method applied in the Irish context and reflects on the added value of using a citizen panel in the development of an HSPA framework.

Methods

A panel of 15 citizens was convened, recruited by a third-party company using a sampling strategy to achieve a balanced mix representing the Irish society. Panellists received lay-language preparatory materials before the meeting. Panellists used a three-colour scheme to signal the importance of performance measures. An exit questionnaire was administered to understand how participants experienced being part of the panel. The citizen panel was the first in a series of three panels towards the development of the HSPA framework, followed by panels including representatives of the DoH and HSE, and representatives from professional associations and special interest groups.

Results

The citizen panel generated 249 health performance measures ranging across 13 domains. Top-ranking domains to the citizen panel (people-centredness, coordination of care, and coverage) were less prioritized by the other panels; domains less prioritized by the citizen panel, such as accessibility, responsiveness, efficiency, and effectiveness, were of higher priority in the other panels. Citizen panellists shared a similar understanding of what a citizen panel involves and described their experience at the panel as enjoyable, interesting, and informative.

Conclusions

The priorities of the citizen panel were accounted for during all phases of developing the HSPA framework. This was possible by adopting an inclusive development process and by engaging citizens early on. Citizen engagement in HSPA development is essential for realizing citizen-driven healthcare system performance and generating trust and ownership in performance intelligence. Future research could expand the use of citizen panels to assess, monitor, and report on the performance of healthcare systems.
Dynamic transcriptome analysis reveals signatures of paradoxical effect of vemurafenib on human dermal fibroblasts
Authors: Corrales Eyleen , Levit-Zerdoun Ella , Metzger Patrick , Kowar Silke , Ku Manching , Brummer Tilman , Boerries Melanie
Published: December 2021

Background

Vemurafenib (PLX4032) is one of the most frequently used treatments for late-stage melanoma patients with the BRAFV600E mutation; however, acquired resistance to the drug poses as a major challenge. It remains to be determined whether off-target effects of vemurafenib on normal stroma components could reshape the tumor microenvironment in a way that contributes to cancer progression and drug resistance.

Methods

By using temporally-resolved RNA- and ATAC-seq, we studied the early molecular changes induced by vemurafenib in human dermal fibroblast (HDF), a main stromal component in melanoma and other tumors with high prevalence of BRAFV600 mutations.

Results

Transcriptomics analyses revealed a stepwise up-regulation of proliferation signatures, together with a down-regulation of autophagy and proteolytic processes. The gene expression changes in HDF strongly correlated in an inverse way with those in BRAFV600E mutant malignant melanoma (MaMel) cell lines, consistent with the observation of a paradoxical effect of vemurafenib, leading to hyperphosphorylation of MEK1/2 and ERK1/2. The transcriptional changes in HDF were not strongly determined by alterations in chromatin accessibility; rather, an already permissive chromatin landscape seemed to facilitate the early accessibility to MAPK/ERK-regulated transcription factor binding sites. Combinatorial treatment with the MEK inhibitor trametinib did not preclude the paradoxical activation of MAPK/ERK signaling in HDF. When administered together, vemurafenib partially compensated for the reduction of cell viability and proliferation induced by trametinib. These paradoxical changes were restrained by using the third generation BRAF inhibitor PLX8394, a so-called paradox breaker compound. However, the advantageous effects on HDF during combination therapies were also lost.

Conclusions

Vemurafenib induces paradoxical changes in HDF, enabled by a permissive chromatin landscape. These changes might provide an advantage during combination therapies, by compensating for the toxicity induced in stromal cells by less specific MAPK/ERK inhibitors. Our results highlight the relevance of evaluating the effects of the drugs on non-transformed stromal components, carefully considering the implications of their administration either as mono- or combination therapies.
Interleukin-1 receptor antagonist inhibits metastatic potential by down-regulating CXCL12/CXCR4 signaling axis in colorectal cancer
Authors: Ma Jiachi , Liang Wanqing , Qiang Yaosheng , Li Lei , Du Jun , Pan Chengwu , Chen Bangling , Zhang Chensong , Chen Yuzhong , Wang Qingkang
Published: December 2021

Background

The aim of this study was to investigate the co-operative role of CXCR4/CXCL12 axis and IL-1Ra in metastatic processes mechanism by interactions between colorectal cancer cells and stromal cells in their microenvironment.

Methods

Expression of IL-1α, interleukin-1 receptor type I (IL-1 RI), CXCL12 and CXCR4 mRNA and proteins were determined by RT-PCR and Western blot. The effect of secreted level of CXCL12 by IL-1Ra on fibroblasts was measured by ELISA. CXCL12 regulate metastatic potential of colorectal cancer was evaluated by proliferation, invasion and angiogenesis assays, respectively, in which invasion and angiogenesis assays used an in vitro system consisting of co-cultured colorectal cells and stromal cells.

Results

IL-1α was expressed in high liver metastatic colorectal cancer cell lines (HT-29 and WiDr). The colorectal cancer cell-derived IL-1α and rIL-1α significantly promoted CXCL12 expression by fibroblasts, and this enhancing effect can be significantly inhibited by IL-1Ra (P < 0.01). CXCL12 not only enhanced the migration and proliferation of human umbilical vein endothelial cells, but also significantly enhanced angiogenesis (P < 0.01). Furthermore, the high liver-metastatic colorectal cancer cell line (HT-29), which secretes IL-1α, significantly enhanced angiogenesis compared to the low liver-metastatic cell line (CaCo-2), which does not produce IL-1α (P < 0.01). On the contrary, IL-1Ra can significantly inhibit migration, proliferation and angiogenesis (P < 0.01).

Conclusion

Autocrine IL-1α and paracrine CXCL12 co-enhances the metastatic potential of colorectal cancer cells; IL-1Ra can inhibit the metastatic potential of colorectal cancer cells via decrease IL-1α/CXCR4/CXCL12 signaling pathways.

Graphical Abstract
SIRT5 functions as a tumor suppressor in renal cell carcinoma by reversing the Warburg effect
Authors: Yihan Liu , Xiaojing Wang , Ao Liu , Chuanjie Zhang , Haofei Wang , Yan Shen , Hongchao He
Published: December 2021

Background

The aim of this study was to investigate the biological functions and underlying mechanisms of SIRT5 in clear cell renal cell carcinoma (ccRCC).

Methods

SIRT5 expression data in The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) were selected, and the correlations between SIRT5 expression and various clinicopathological parameters were analysed. SIRT5 expression in ccRCC tissues was examined using immunohistochemistry. Stable cell lines with SIRT5 knockdown were established. In vitro and in vivo experiments were conducted to investigate the functional roles of SIRT5 in the cellular biology of ccRCC, including cell viability assays, wound healing assays, soft agar colony formation assays, Transwell invasion assays, qRT–PCR, and Western blotting. In addition, microarrays, rescue experiments and Western blotting were used to investigate the molecular mechanisms underlying SIRT5 functions.

Results

SIRT5 expression was downregulated in ccRCC compared with normal tissues, which correlated with a poor prognosis of ccRCC. SIRT5 knockdown significantly increased cell proliferation, migration and invasion in vitro. In vivo experiments revealed that SIRT5 knockdown promoted ccRCC tumorigenesis and metastasis. Mechanistically, SIRT5 deglycosylated PDHA1 at K351 and increased PDC activity, thereby altering the metabolic crosstalk with the TCA cycle and inhibiting the Warburg effect. SIRT5 overexpression was related to low succinylation of PDHA1.

Conclusions

Downregulated SIRT5 expression in ccRCC accelerated the Warburg effect through PDHA1 hypersuccinylation and induced tumorigenesis and progression, indicating that SIRT5 may become a potential target for ccRCC therapy.
NOX4: a potential therapeutic target for pancreatic cancer and its mechanism
Authors: Bi Yawei , Lei Xiao , Chai Ningli , Linghu Enqiang
Published: December 2021

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is one of the seven isoforms of NOX family, which is upregulated in pancreatic cancer cell, mouse model of pancreatic cancer and human pancreatic cancer tissue. NOX4 is a constitutively active enzyme that primarily produces hydrogen peroxide, which exhibits completely different properties from other subtypes of NOX family. More importantly, recent studies illuminate that NOX4 promotes pancreatic cancer occurrence and development in different ways. This review summarizes the potential roles and its mechanism of NOX4 in pancreatic cancer and explores NOX4 as the potential therapeutic target in pancreatic cancer.
Influence of the trajectory of the urine output for 24 h on the occurrence of AKI in patients with sepsis in intensive care unit
Authors: Zhang Luming , Xu Fengshuo , Han Didi , Huang Tao , Li Shaojin , Yin Haiyan , Lyu Jun
Published: December 2021

Background

Sepsis-associated acute kidney injury (S-AKI) is a common and life-threatening complication in hospitalized and critically ill patients. This condition is an independent cause of death. This study was performed to investigate the correlation between the trajectory of urine output within 24 h and S-AKI.

Methods

Patients with sepsis were studied retrospectively based on the Medical Information Mart for Intensive Care IV. Latent growth mixture modeling was used to classify the trajectory of urine output changes within 24 h of sepsis diagnosis. The outcome of this study is AKI that occurs 24 h after sepsis. Cox proportional hazard model, Fine–Gray subdistribution proportional hazard model, and doubly robust estimation method were used to explore the risk of AKI in patients with different trajectory classes.

Results

A total of 9869 sepsis patients were included in this study, and their 24-h urine output trajectories were divided into five classes. The Cox proportional hazard model showed that compared with class 1, the HR (95% CI) values for classes 3, 4, and 5 were 1.460 (1.137–1.875), 1.532 (1.197–1.961), and 2.232 (1.795–2.774), respectively. Competing risk model and doubly robust estimation methods reached similar results.

Conclusions

The trajectory of urine output within 24 h of sepsis patients has a certain impact on the occurrence of AKI. Therefore, in the early treatment of sepsis, close attention should be paid to changes in the patient's urine output to prevent the occurrence of S-AKI.
Surgical outcomes in children under 10 years old in the treatment of congenital scoliosis due to single nonincarcerated thoracolumbar hemivertebra: according to the age at surgery
Authors: Li Haixia , Chen Zhiming , Gao Bo , Wang Jiaxu , Shao Shuilin , Wu Jigong
Published: December 2021

Purpose

Hemivertebra is one of the common pathogenesis of congenital scoliosis. The timing of operation is undefined. Our study compared the surgical outcomes in children under age 10 years with scoliosis due to single nonincarcerated thoracolumbar hemivertebra according to the age at surgery.

Methods

From January 2009 to August 2017, we retrospectively investigated 34 consecutive cases of congenital scoliosis treated by posterior hemivertebra resection and fusion with pedicle screw fixation. All cases were divided into two groups according to the age at surgery and followed-up for at least 2 years, group 1 (≤ 5 years old), and group 2 (5 to 10 years old).

Results

The mean Cobb angle of the main curve was improved from 48.58° to 15.53° (68.05%) in group 1, and from 43.73° to 11.33° (75.43%) in group 2. The segmental curve was improved from 44.16° to 11.53° (74.64%) in group 1, and the segmental curve was consistent with the main curve in group 2. The mean segmental kyphosis was improved from 27.50° to 8.42° (67.40%) in group 1, and from 29.00° to 5.00° (84.73%) in group 2. Five patients developed distal adding-on, and four patients were found proximal junctional kyphosis during the follow-up.

Conclusion

Not all the deformities caused by single nonincarcerated thoracolumbar hemivertebra would progress greatly with the spinal growth. No significant statistical differences were found in the coronal and sagittal correction rate between the two groups. A limited delayed surgery after 5 years but before 10 years of age with close follow-up can achieve satisfied results.
The oncogenic kinase NEK2 regulates an RBFOX2-dependent pro-mesenchymal splicing program in triple-negative breast cancer cells
Authors: Naro Chiara , De Musso Monica , Delle Monache Francesca , Panzeri Valentina , de la Grange Pierre , Sette Claudio
Published: December 2021

Background

Triple-negative breast cancer (TNBC) is the most heterogeneous and malignant subtype of breast cancer (BC). TNBC is defined by the absence of expression of estrogen, progesterone and HER2 receptors and lacks efficacious targeted therapies. NEK2 is an oncogenic kinase that is significantly upregulated in TNBC, thereby representing a promising therapeutic target. NEK2 localizes in the nucleus and promotes oncogenic splice variants in different cancer cells. Notably, alternative splicing (AS) dysregulation has recently emerged as a featuring trait of TNBC that contributes to its aggressive phenotype.

Methods

To investigate whether NEK2 modulates TNBC transcriptome we performed RNA-sequencing analyses in a representative TNBC cell line (MDA-MB-231) and results were validated in multiple TNBC cell lines. Bioinformatics and functional analyses were carried out to elucidate the mechanism of splicing regulation by NEK2. Data from The Cancer Genome Atlas were mined to evaluate the potential of NEK2-sensitive exons as markers to identify the TNBC subtype and to assess their prognostic value.

Results

Transcriptome analysis revealed a widespread impact of NEK2 on the transcriptome of TNBC cells, with 1830 AS events that are susceptible to its expression. NEK2 regulates the inclusion of cassette exons in splice variants that discriminate TNBC from other BC and that correlate with poor prognosis, suggesting that this kinase contributes to the TNBC-specific splicing program. NEK2 elicits its effects by modulating the expression of the splicing factor RBFOX2, a well-known regulator of epithelial to mesenchymal transition (EMT). Accordingly, NEK2 splicing-regulated genes are enriched in functional terms related to cell adhesion and contractile cytoskeleton and NEK2 depletion in mesenchymal TNBC cells induces phenotypic and molecular traits typical of epithelial cells. Remarkably, depletion of select NEK2-sensitive splice-variants that are prognostic in TNBC patients is sufficient to interfere with TNBC cell morphology and motility, suggesting that NEK2 orchestrates a pro-mesenchymal splicing program that modulates migratory and invasive properties of TNBC cells.

Conclusions

Our study uncovers an extensive splicing program modulated by NEK2 involving splice variants that confer an invasive phenotype to TNBCs and that might represent, together with NEK2 itself, valuable therapeutic targets for this disease.
The prognostic factor for recurrence in advanced-stage high-grade serous ovarian cancer after complete clinical remission: a nested case-control study
Authors: Wang Qiao , Zheng Ying , Wang Ping , Zhang Jiawen , Liu Hui , Li Qingli , Yin Rutie , Bian Ce , Peng Hongling , Peng Zhilan
Published: December 2021

Background

Women with advanced-stage high-grade serous ovarian cancer (HGSOC) are likely to have a bad prognosis. Relapses are common in patients even with no evidence of disease after primary treatment. We aimed to identify the prognostic factors for disease recurrence in these patients.

Methods

A nested case-control study was conducted in a large medical center in Southwest China. The primary outcome was recurrence of disease within 3 years after clinical remission (CR). Cox regression was used to calculate the time to event analysis in different groups.

Results

Ninety-seven patients were finally included. Fifty-seven patients (58.8%) relapsed within 3 years after CR. Among all the variables, the difference in posttreatment CA-125 level was statistically significant (P <0.05) between the recurrent group and the progression-free group in both univariate and multivariable analysis. A cutoff value was set at the median level in the recurrent group (10 U/ml) to categorize patients into two arms. In Cox regression, the posttreatment CA-125 level was identified as a prognostic factor for recurrence with an OR of 1.05 (95% CI: 1.02–1.10, P = 0.033). The median time (from initiation of treatment) until relapse was 25 months for patients whose posttreatment CA-125 levels were higher than 10 U/ml, while it was undefined for patients whose posttreatment CA-125 level were ≤ 10 U/ml. Patients with a higher posttreatment CA-125 level showed an increased risk for OC relapse compared to those with a lower posttreatment CA-125 level. Furthermore, as shown in line graphs recording serum CA-125 levels during follow-up in each recurrent case, the increments of serum CA-125 levels were delayed in recurrent OC patients who had a posttreatment CA125 level ≤ 10 U/ml compared with those with a higher CA-125 level.

Conclusion

A low serum CA-125 level after primary treatment was a potential prognostic factor in women with advanced HGSOC.
Intraosseous fluid resuscitation causes systemic fat emboli in a porcine hemorrhagic shock model
Authors: Kristiansen Steinar , Storm Benjamin , Dahle Dalia , Domaas Josefsen Terje , Dybwik Knut , Nilsen Bent Aksel , Waage-Nielsen Erik
Published: December 2021

Background

Intraosseous cannulation can be life-saving when intravenous access cannot be readily achieved. However, it has been shown that the procedure may cause fat emboli to the lungs and brain. Fat embolization may cause serious respiratory failure and fat embolism syndrome. We investigated whether intraosseous fluid resuscitation in pigs in hemorrhagic shock caused pulmonary or systemic embolization to the heart, brain, or kidneys and if this was enhanced by open chest conditions.

Methods

We induced hemorrhagic shock in anesthetized pigs followed by fluid-resuscitation through bilaterally placed tibial (hind leg) intraosseous cannulas. The fluid-resuscitation was limited to intraosseous or i.v. fluid therapy, and did not involve cardiopulmonary resuscitation or other interventions. A subgroup underwent median sternotomy with pericardiectomy and pleurotomy before hemorrhagic shock was induced. We used invasive hemodynamic and respiratory monitoring including Swan Ganz pulmonary artery catheter and transesophageal echocardiography and obtained biopsies from the lungs, heart, brain, and left kidney postmortem.

Results

All pigs exposed to intraosseous infusion had pulmonary fat emboli in postmortem biopsies. Additionally, seven of twenty-one pigs had coronary fat emboli. None of the pigs with open chest had fat emboli in postmortem lung, heart, or kidney biopsies. During intraosseous fluid-resuscitation, three pigs developed significant ST-elevations on ECG; all of these animals had coronary fat emboli on postmortem biopsies.

Conclusions

Systemic fat embolism occurred in the form of coronary fat emboli in a third of the animals who underwent intraosseous fluid resuscitation. Open chest conditions did not increase the incidence of systemic fat embolization.
Low thyroid hormone receptor alpha-2 (THRα-2) tumor expression is associated with unfavorable tumor characteristics and high breast cancer mortality
Authors: Sandsveden Malte , Borgquist Signe , Rosendahl Ann H. , Manjer Jonas
Published: December 2021

Background

The active thyroid hormone triiodothyronine (T3) has been found to have an estrogen-like effect on breast cancer cells. Thyroid hormone receptor alpha-2 (THRα-2) acts as an antagonist for triiodothyronine (T3) signaling, and a low expression has been associated with unfavorable tumor characteristics and a higher mortality in breast cancer. However, the evidence are not conclusive. The present study evaluates tumor-specific THRα-2 expression in invasive breast cancers and its association with tumor characteristics and long-term mortality in a large population.

Method

The Malmö Diet and Cancer Study (MDCS), a population-based cohort in Sweden that included 17,035 women from 1991 to 1996, was used. Women diagnosed with breast cancer during 1991–2010 were eligible for inclusion. A tissue micro array was constructed from stored tumor material and stained for THRα-2 using immunohistochemistry. Tumors from 654 patients were scored regarding the intensity and the fraction of cells stained, then dichotomized into low or high expression. Date and cause of death were collected up until 2018-12-31. Tumor- and patient characteristics were available from the MDCS. Missing data was imputed using chained equations. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for low vs high expression of THRα-2 related to specific tumor factors. Mortality was evaluated with Kaplan–Meier curves and Cox regression, rendering hazard ratios (HRs). Analyses were also stratified for estrogen receptor (ER) status.

Results

We found strong evidence of an association between low THRα-2 and unfavorable tumor characteristics, including estrogen receptor negativity: OR 4.04 (95% CI 2.28–7.15) and tumor size > 20–50 mm: OR 2.20 (95% CI 1.39–3.49). We found evidence of increased breast cancer-specific mortality for women with low THRα-2, HR 1.38 (95% CI 0.96–1.99), which remained after adjusting for age at diagnosis, HR 1.48 (95% CI 1.03–2.14), but not after adjusting for relevant prognostic factors, HR 0.98 (95% CI 0.66–1.45). THRα-2 expression in ER-negative tumors had an inverse correlation with overall mortality, HR 0.27 (95% CI 0.11–0.65).

Conclusion

Low tumor-specific THRα-2 expression was in this study associated with prognostically unfavorable tumor characteristics and a higher mortality in breast cancer, but not independent from other prognostic factors.
SCEPTRE improves calibration and sensitivity in single-cell CRISPR screen analysis
Authors: Barry Timothy , Wang Xuran , Morris John A. , Roeder Kathryn , Katsevich Eugene
Published: December 2021

Single-cell CRISPR screens are a promising biotechnology for mapping regulatory elements to target genes at genome-wide scale. However, technical factors like sequencing depth impact not only expression measurement but also perturbation detection, creating a confounding effect. We demonstrate on two single-cell CRISPR screens how these challenges cause calibration issues. We propose SCEPTRE: analysis of single-cell perturbation screens via conditional resampling, which infers associations between perturbations and expression by resampling the former according to a working model for perturbation detection probability in each cell. SCEPTRE demonstrates very good calibration and sensitivity on CRISPR screen data, yielding hundreds of new regulatory relationships supported by orthogonal biological evidence.
Salivary gland ultrasonography in primary Sjögren’s syndrome from diagnosis to clinical stratification: a multicentre study
Authors: Zhang Xia , Feng Ruiling , Zhao Jinxia , Wang Yu , He Juan , Liu Li , Cheng Yongjing , Yao Haihong , Tang Sumei , Chen Jiali , Zhang Shanshan , Zhang Zhiyi , Wang Qingwen , He Jing , Li Zhanguo
Published: December 2021

Background

To determine the diagnostic accuracy of major salivary gland ultrasonography (SGUS) in primary Sjögren’s syndrome (pSS) using the novel Outcome Measures in Rheumatology Clinical Trials (OMERACT) scoring system in a large-scale multicentre study.

Methods

SGUS was conducted for 246 pSS patients, 140 control subjects with conditions other than SS and 27 healthy control subjects. The echostructure features from the parotid and submandibular glands on both sides were graded using the novel OMERACT scoring system. Receiver operating characteristic curves were used to describe the diagnostic accuracy of the scoring system for pSS. The associations between the SGUS and disease characteristics were analysed to evaluate the clinical value of SGUS for pSS.

Results

The US scores in the pSS group were significantly higher than those in the non-pSS group (p < 0.001). The level of diagnostic accuracy was comparable with the scores of all four glands (AUC=0.908) when only the parotid and submandibular glands on either side were scored (AUC=0.910, 0.904, respectively). The optimal cut-off value for the left (right) parotid gland and the left (right) submandibular gland was 4, with maximal sensitivity (75.6% and 77.2%, respectively) and specificity (91.6% and 92.2%, respectively). The pSS patients with positive SGUS results presented a longer disease duration, parotid enlargement, dental loss and higher levels of serological markers, such as anti-SSA, anti-SSB, positive RF, IgG and γ-globulin%.

Conclusions

SGUS with the OMERACT scoring system yields high sensitivity and specificity, demonstrating high diagnostic feasibility for pSS. The SGUS may have implications for deciding disease severity and treatment efficacy.
Genomic characterization of bacteriophage BI-EHEC infecting strains of Enterohemorrhagic Escherichia coli
Authors: Dewanggana Marta Nisita , Waturangi Diana Elizabeth , Yogiara
Published: December 2021

Objective

The aims of this research were to determine the genomic properties of BI-EHEC to control Enterohemorrhagic Escherichia coli (EHEC), which was isolated from previous study. Genomic analysis of this phage is essential for the assessment of this bacteriophage for further application as food preservatives.

Results

Genome of BI-EHEC was successfully annotated using multiPhATE2. Structural and lytic cycle-related proteins such as head, tail, capsid, and lysozyme (lysin) were annotated. The phylogenetic tree of tail fiber protein and BRIG results showed that BI-EHEC was similar to phages of the same host in the bacteriophage genome database. There were no indications of virulence properties, antibiotic resistance genes and lysogenic protein among annotated genes which implied BI-EHEC followed a lytic life cycle. PHACTS analysis was done to confirm this notion further and yielded a lytic cycle result. Further analysis using CARD found that BI-EHEC does not contain residual ARGs per recommended parameter. Furthermore, BI-EHEC confirmed as lytic bacteriophage, making it a good candidate for biocontrol agent.
Reproductive history and blood cell DNA methylation later in life: the Young Finns Study
Authors: Harville Emily W. , Mishra Pashupati P. , Kähönen Mika , Raitoharju Emma , Marttila Saara , Raitakari Olli , Lehtimäki Terho
Published: December 2021

Background

Women with a history of complications of pregnancy, including hypertensive disorders, gestational diabetes or an infant fetal growth restriction or preterm birth, are at higher risk for cardiovascular disease later in life. We aimed to examine differences in maternal DNA methylation following pregnancy complications.

Methods

Data on women participating in the Young Finns study (n = 836) were linked to the national birth registry. DNA methylation in whole blood was assessed using the Infinium Methylation EPIC BeadChip. Epigenome-wide analysis was conducted on differential CpG methylation at 850 K sites. Reproductive history was also modeled as a predictor of four epigenetic age indices.

Results

Fourteen significant differentially methylated sites were found associated with both history of pre-eclampsia and overall hypertensive disorders of pregnancy. No associations were found between reproductive history and any epigenetic age acceleration measure.

Conclusions

Differences in epigenetic methylation profiles could represent pre-existing risk factors, or changes that occurred as a result of experiencing these complications.
DZNep promotes mouse bone defect healing via enhancing both osteogenesis and osteoclastogenesis
Authors: Cao Xiankun , He Wenxin , Rong Kewei , Xu Shenggui , Chen Zhiqian , Liang Yuwei , Han Shuai , Zhou Yifan , Yang Xiao , Ma Hui , Qin An , Zhao Jie
Published: December 2021

Background

Enhancer of zeste homolog 2 (EZH2) is a novel oncogene that can specifically trimethylate the histone H3 lysine 27 (H3K27me3) to transcriptionally inhibit the expression of downstream tumor-suppressing genes. As a small molecular inhibitor of EZH2, 3-Deazaneplanocin (DZNep) has been widely studied due to the role of tumor suppression. With the roles of epigenetic regulation of bone cells emerged in past decades, the property and molecular mechanism of DZNep on enhancing osteogenesis had been reported and attracted a great deal of attention recently. This study aims to elucidate the role of DZNep on EZH2-H3K27me3 axis and downstream factors during both osteoclasts and osteoblasts formation and the therapeutic possibility of DZNep on bone defect healing.

Methods

Bone marrow-derived macrophages (BMMs) cells were cultured, and their responsiveness to DZNep was evaluated by cell counting kit-8, TRAP staining assay, bone resorption assay, podosome actin belt. Bone marrow-derived mesenchymal stem cells (BMSC) were cultured and their responsiveness to DZNep was evaluated by cell counting kit-8, ALP and AR staining assay. The expression of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), Wnt signaling pathway was determined by qPCR and western blotting. Mouse bone defect models were created, rescued by DZNep injection, and the effectiveness was evaluated by X-ray and micro-CT and histological staining.

Results

Consistent with the previous study that DZNep enhances osteogenesis via Wnt family member 1(Wnt1), Wnt6, and Wnt10a, our results showed that DZNep also promotes osteoblasts differentiation and mineralization through the EZH2-H3K27me3-Wnt4 axis. Furthermore, we identified that DZNep promoted the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation via facilitating the phosphorylation of IKKα/β, IκB, and subsequently NF-κB nuclear translocation, which credit to the EZH2-H3K27me3-Foxc1 axis. More importantly, the enhanced osteogenesis and osteoclastogenesis result in accelerated mice bone defect healing in vivo.

Conclusion

DZNep targeting EZH2-H3K27me3 axis facilitated the healing of mice bone defect via simultaneously enhancing osteoclastic bone resorption and promoting osteoblastic bone formation.