bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences in lipid metabolism in acquired versus preexisting glucose intolerance during gestation: role of free fatty acids and sphingosine-1-phosphate
Authors: Liebmann Moritz , Grupe Katharina , Asuaje Pfeifer Melissa , Rustenbeck Ingo , Scherneck Stephan
Published: October 2022

Background

The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. There is increasing evidence that GDM is a heterogeneous disease with different subtypes. An important question in this context is whether impaired glucose tolerance (IGT), which is a typical feature of the disease, may already be present before pregnancy and manifestation of the disease. The latter type resembles in its clinical manifestation prediabetes that has not yet manifested as type 2 diabetes (T2DM). Altered lipid metabolism plays a crucial role in the disorder's pathophysiology. The aim was to investigate the role of lipids which are relevant in diabetes-like phenotypes in these both models with different time of initial onset of IGT.

Methods

Two rodent models reflecting different characteristics of human GDM were used to characterize changes in lipid metabolism occurring during gestation. Since the New Zealand obese (NZO)-mice already exhibit IGT before and during gestation, they served as a subtype model for GDM with preexisting IGT (preIGT) and were compared with C57BL/6 N mice with transient IGT acquired during gestation (aqIGT). While the latter model does not develop manifest diabetes even under metabolic stress conditions, the NZO mouse is prone to severe disease progression later in life. Metabolically healthy Naval Medical Research Institute (NMRI) mice served as controls.

Results

In contrast to the aqIGT model, preIGT mice showed hyperlipidemia during gestation with elevated free fatty acids (FFA), triglycerides (TG), and increased atherogenic index. Interestingly, sphingomyelin (SM) concentrations in the liver decreased during gestation concomitantly with an increase in the sphingosine-1-phosphate (S1P) concentration in plasma. Further, preIGT mice showed impaired hepatic weight adjustment and alterations in hepatic FFA metabolism during gestation. This was accompanied by decreased expression of peroxisome proliferator-activated receptor alpha (PPARα) and lack of translocation of fatty acid translocase (FAT/CD36) to the hepatocellular plasma membrane.

Conclusion

The preIGT model showed impaired lipid metabolism both in plasma and liver, as well as features of insulin resistance consistent with increased S1P concentrations, and in these characteristics, the preIGT model differs from the common GDM subtype with aqIGT. Thus, concomitantly elevated plasma FFA and S1P concentrations, in addition to general shifts in sphingolipid fractions, could be an interesting signal that the metabolic disorder existed before gestation and that future pregnancies require more intensive monitoring to avoid complications.

Graphical Abstract

This graphical abstract was created with BioRender.com.
FGF15 promotes hepatic NPC1L1 degradation in lithogenic diet-fed mice
Authors: Mo Pingfan , Chen Hongtan , Jiang Xin , Hu Fengling , Zhang Fenming , Shan Guodong , Chen Wenguo , Li Sha , Li Yiqiao , Xu Guoqiang
Published: October 2022

Background

Cholesterol gallstone disease (CGD) is accompanied by biliary cholesterol supersaturation. Hepatic Niemann-Pick C1-like 1 (NPC1L1), which is present in humans but not in wild-type (WT) mice, promotes hepatocyte cholesterol uptake and decreases biliary cholesterol supersaturation. In contrast, intestinal NPC1L1 promotes intestinal cholesterol absorption, increasing biliary cholesterol supersaturation. Ezetimibe (EZE) can inhibit both hepatic and intestinal NPC1L1. However, whether hepatic NPC1L1 can affect CGD progress remains unknown.

Methods

Mice expressing hepatic NPC1L1 (NPC1L1hepatic-OE mice) were generated using Adeno-associated viruses (AAV) gene delivery. The protein level and function of hepatic NPC1L1 were examined under chow diet, high fat-cholesterol diet (HFCD), and lithogenic diet (LD) feeding. Gallstone formation rates were examined with or without EZE treatment. Fibroblast growth factor 15 (FGF15) treatment and inhibition of fibroblast growth factor receptor 4 (FGFR4) were applied to verify the mechanism of hepatic NPC1L1 degradation.

Results

The HFCD-fed NPC1L1hepatic-OE mice retained the biliary cholesterol desaturation function of hepatic NPC1L1, whereas EZE treatment decreased biliary cholesterol saturation and did not cause CGD. The ubiquitination and degradation of hepatic NPC1L1 were discovered in LD-fed NPC1L1hepatic-OE mice. Treatment of FGF15 during HFCD feeding and inhibition of FGFR4 during LD feeding could affect the protein level and function of hepatic NPC1L1.

Conclusions

LD induces the ubiquitination and degradation of hepatic NPC1L1 via the FGF15-FGFR4 pathway. EZE may act as an effective preventative agent for CGD.
Potential novel biomarkers in small intestine for obesity/obesity resistance revealed by multi-omics analysis
Authors: Pang Yueshan , Zheng Yali , Yang Ni , Zan Meng , Zhang Lu , Ding WeiJun
Published: October 2022

Background

Although obesity is caused by different factors, individual susceptibility to obesity differs among people under the same circumstances. The microbiota in the caecum or fresh faeces and metabolites in blood or urine contribute to obesity resistance; however, the microbiota or metabolites in the small intestine have not been extensively studied.

Methods

To investigate the relationship between the microbiota or metabolites in the small intestine and susceptibility to obesity, eighty-eight male C57BL/6 mice were fed a high-fat diet (HFD) for 8 weeks to establish two models of obesity and obesity resistance. For further study, six mice were chosen from among the obesity models, and twelve mice were randomly chosen from among the obesity resistance models. After fasting plasma glucose and behavioural testing, the mice were fed in single cages for another 4 weeks to observe their weight and food intake. All mice were sacrificed at 20 weeks of age. Serum ALT, AST, HDL, LDL, TG and TC levels were measured using an automatic biochemical analyser. The microbiota and metabolites in the small intestine contents were analysed using 16 S sequencing and an ultrahigh-performance liquid chromatographic system, respectively. Transcripts in the jejunum were evaluated using full-length transcriptome sequencing and verified by qPCR.

Results

The results showed that HFD induced depression and anxiety behaviours and higher fasting plasma glucose, ALT, AST, HDL, LDL, TG and TC levels in the obese mice; however, these levels were improved in obese resistance mice. The correlation analysis showed that the phosphatidylcholine, TG, and phosphatidylethanolamine levels were higher in obese mice and correlated positively with intestinal microflora (Desulfovibrio and Gemella) and the Cxcl10 gene. A higher abundance of Clostridium_sensu_stricto_1 in obesity-resistant mice correlated negatively with the metabolite contents (neuromedin N and enkephalin L) and Pck1 gene expression and correlated positively with certain metabolites (5-hydroxy-L-tryptophan, cinnamyl alcohol and 1 H-indole-3-acetamide) and genes expression (Gdf15, Igfbp6 and Spp1).

Conclusion

Clostridium_sensu_stricto_1, neuromedin N, enkephalin L, Pck1, 5-hydroxy-L-tryptophan, Cxcl10 and cinnamyl alcohol may be novel biomarkers in the small intestine for obesity/obesity resistance. These might be helpful for obesity prevention or for treating obese patients.
Biologically synthesized black ginger-selenium nanoparticle induces apoptosis and autophagy of AGS gastric cancer cells by suppressing the PI3K/Akt/mTOR signaling pathway
Authors: Wang Rongbo , Ha Keum-yun , Dhandapani Sanjeevram , Kim Yeon-Ju
Published: October 2022

Background

Despite being a promising strategy, current chemotherapy for gastric cancer (GC) is limited due to adverse side effects and poor survival rates. Therefore, new drug-delivery platforms with good biocompatibility are needed. Recent studies have shown that nanoparticle-based drug delivery can be safe, eco-friendly, and nontoxic making them attractive candidates. Here, we develop a novel selenium-nanoparticle based drug-delivery agent for cancer treatment from plant extracts and selenium salts.

Results

Selenium cations were reduced to selenium nanoparticles using Kaempferia parviflora (black ginger) root extract and named KP-SeNP. Transmission electron microscopy, selected area electron diffraction, X-ray diffraction, energy dispersive X-ray, dynamic light scattering, and Fourier-transform infrared spectrum were utilized to confirm the physicochemical features of the nanoparticles. The KP-SeNPs showed significant cytotoxicity in human gastric adenocarcinoma cell (AGS cells) but not in normal cells. We determined that the intracellular signaling pathway mechanisms associated with the anticancer effects of KP-SeNPs involve the upregulation of intrinsic apoptotic signaling markers, such as B-cell lymphoma 2, Bcl-associated X protein, and caspase 3 in AGS cells. KP-SeNPs also caused autophagy of AGS by increasing the autophagic flux-marker protein, LC3B-II, whilst inhibiting autophagic cargo protein, p62. Additionally, phosphorylation of PI3K/Akt/mTOR pathway markers and downstream targets was decreased in KP-SeNP-treated AGS cells. AGS-cell xenograft model results further validated our in vitro findings, showing that KP-SeNPs are biologically safe and exert anticancer effects via autophagy and apoptosis.

Conclusions

These results show that KP-SeNPs treatment of AGS cells induces apoptosis and autophagic cell death through the PI3K/Akt/mTOR pathway, suppressing GC progression. Thus, our research strongly suggests that KP-SeNPs could act as a novel potential therapeutic agent for GC.

Graphical Abstract
Intracellular mRNA phase separation induced by cationic polymers for tumor immunotherapy
Authors: Xing Zhen , Xue Jing , Ma Xindian , Han Congwei , Wang Zhenzhen , Luo Shunhuang , Wang Chunming , Dong Lei , Zhang Junfeng
Published: October 2022

The formation of biomolecular condensates via liquid‒liquid phase separation (LLPS) is an advantageous strategy for cells to organize their subcellular compartments for diverse functions. Recent findings suggest that RNA or RNA-related LLPS techniques have potential for the development of new cellular regulation strategies. However, manipulating RNA LLPS in living cells has great challenges. Herein, we report that cationic polymers (CPs) have strong RNA LLPS-inducing activity. By introducing CPs into living cells or RNA solutions, significant RNA LLPS was verified through confocal imaging, turbidity assays, and fluorescence recovery after photobleaching (FRAP) tests. Among them, turbidity kinetics determinations indicated that the hydrophilic positively charged amino groups on the CPs play essential roles in RNA phase separation. Moreover, the LLPS induced by the cationic polymers dramatically changed the gene expression patterns in the cells. Interestingly, we found that TGFβ1 mRNA was highly encapsulated in the RNA droplets, which lowered the immunosuppressive capability of the tumor cells and triggered marked antitumor reactions in a mouse breast cancer model. Thus, we present here the CP-based modulation of RNA LLPS as a novel transcriptional manipulation method with potential for cancer immunotherapy drug development.

Graphical Abstract
Nurses’ steps, distance traveled, and perceived physical demands in a three-shift schedule
Authors: Chang Hyoung Eun , Cho Sung-Hyun
Published: October 2022

Background

The physical job demands of hospital nurses are known to be very high. Although many studies have measured the physical activities of nurses subjectively using questionnaires, it remains necessary to quantify and measure nurses’ physical activity at work using objective indicators. This study was conducted to address this gap in the literature by analyzing nurses’ physical activity using both objective measurements and subjective perceptions. The number of steps, distance traveled, and actual work hours were measured during work, and the influence of related factors was analyzed.

Methods

Using a cross-sectional design, survey and activity tracking data were collected from nurses who worked in three shifts in two tertiary hospitals located in the capital region of South Korea. The participants comprised 117 nurses working in four different units (medical ward, surgical ward, intensive care unit, emergency room), and data from 351 shifts were used in the final analysis. Between-group differences in the main variables were analyzed using the t-test, the Mann–Whitney test, analysis of variance, or the Kruskal–Wallis test, as appropriate. The relationships were examined through multiple linear regression analysis.

Results

The average number of steps and distance traveled were greatest for nurses working in the emergency room, followed by the intensive care unit, surgical ward, and medical ward (in descending order). Younger nurses and those with shorter unit experience tended to have the greatest number of steps and distance traveled.

Conclusion

Using activity trackers, this study derived physical activity measures such as number of steps and distance traveled, enabling an objective examination of physical activity during shifts. Nurses’ level of physical activity differed depending on the type of nursing unit, nurses’ age, and unit experience. These results suggest the need for support programs that are specific to the job demands of specific nursing units.
A framework for considering the utility of models when facing tough decisions in public health: a guideline for policy-makers
Authors: Thompson Jason , McClure Roderick , Scott Nick , Hellard Margaret , Abeysuriya Romesh , Vidanaarachchi Rajith , Thwaites John , Lazarus Jeffrey V. , Lavis John , Michie Susan , Bullen Chris , Prokopenko Mikhail , Chang Sheryl L. , Cliff Oliver M. , Zachreson Cameron , Blakely Antony , Wilson Tim , Ouakrim Driss Ait , Sundararajan Vijay
Published: October 2022

The COVID-19 pandemic has brought the combined disciplines of public health, infectious disease and policy modelling squarely into the spotlight. Never before have decisions regarding public health measures and their impacts been such a topic of international deliberation, from the level of individuals and communities through to global leaders. Nor have models—developed at rapid pace and often in the absence of complete information—ever been so central to the decision-making process. However, after nearly 3 years of experience with modelling, policy-makers need to be more confident about which models will be most helpful to support them when taking public health decisions, and modellers need to better understand the factors that will lead to successful model adoption and utilization. We present a three-stage framework for achieving these ends.
Improving the availability of prescription drugs in Lebanon: a critical analysis of alternative policy options
Authors: El-Harakeh Amena , Haley Sean J.
Published: October 2022

The economic downfall in Lebanon and the destruction of the Beirut Port have had a crippling effect on all players in the health sector, including hospitals, healthcare providers, and the pharmaceutical and medical supply industry. The outbreak of COVID-19 has further aggravated the crisis. To address the challenges facing the pharmaceutical industry, Lebanon must create a stable and secure source of prescription drug production. Two alternative approaches are presented to address the crisis: (1) amending the subsidy system and supporting local pharmaceutical production, and (2) promoting the prescription and use of generic drugs. Investing in local production is promising and can lead to establishing trust in the quality of drugs produced locally. These efforts can be complemented by promoting the prescription and use of generic drugs at a later stage, after having had established a well-operating system for local drug production.
Decoding the colorectal cancer ecosystem emphasizes the cooperative role of cancer cells, TAMs and CAFsin tumor progression
Authors: Shen Rongfang , Li Ping , Zhang Botao , Feng Lin , Cheng Shujun
Published: October 2022

Background

Single-cell transcription data provided unprecedented molecular information, enabling us to directly encode the ecosystem of colorectal cancer (CRC). Characterization of the diversity of epithelial cells and how they cooperate with tumor microenvironment cells (TME) to endow CRC with aggressive characteristics at single-cell resolution is critical for the understanding of tumor progression mechanism.

Methods

In this study, we comprehensively analyzed the single-cell transcription data, bulk-RNA sequencing data and pathological tissue data. In detail, cellular heterogeneity of TME and epithelial cells were analyzed by unsupervised classification and consensus nonnegative matrix factorization analysis, respectively. Functional status of epithelial clusters was annotated by CancerSEA and its crosstalk with TME cells was investigated using CellPhoneDB and correlation analysis. Findings from single-cell transcription data were further validated in bulk-RNA sequencing data and pathological tissue data.

Results

A distinct cellular composition was observed between tumor and normal tissues, and tumors exhibited immunosuppressive phenotypes. Regarding epithelial cells, we identified one highly invasiveQuery cluster, C4, that correlated closely with tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). Further analysis emphasized the TAMs subclass TAM1 and CAFs subclass S5 are closely related with C4.

Conclusions

In summary, our study elaborates on the cellular heterogeneity of CRC, revealing that TAMs and CAFs were critical for crosstalk network epithelial cells and TME cells. This in-depth understanding of cancer cell-TME network provided theoretical basis for the development of new drugs targeting this sophisticated network in CRC.
Pivotal interplays between fecal metabolome and gut microbiome reveal functional signatures in cerebral ischemic stroke
Authors: Zhao Lanlan , Wang Cheng , Peng Shanxin , Zhu Xiaosong , Zhang Ziyi , Zhao Yanyan , Zhang Jinling , Zhao Guoping , Zhang Tao , Heng Xueyuan , Zhang Lei
Published: October 2022

Background

Integrative analysis approaches of metagenomics and metabolomics have been widely developed to understand the association between disease and the gut microbiome. However, the different profiling patterns of different metabolic samples in the association analysis make it a matter of concern which type of sample is the most closely associated with gut microbes and disease. To address this lack of knowledge, we investigated the association between the gut microbiome and metabolomic profiles of stool, urine, and plasma samples from ischemic stroke patients and healthy subjects.

Methods

We performed metagenomic sequencing (feces) and untargeted metabolomics analysis (feces, plasma, and urine) from ischemic stroke patients and healthy volunteers. Differential analyses were conducted to find key differential microbiota and metabolites for ischemic stroke. Meanwhile, Spearman’s rank correlation and linear regression analyses were used to study the association between microbiota and metabolites of different metabolic mixtures.

Results

Untargeted metabolomics analysis shows that feces had the most abundant features and identified metabolites, followed by urine and plasma. Feces had the highest number of differential metabolites between ischemic stroke patients and the healthy group. Based on the association analysis between metagenomics and metabolomics of fecal, urine, and plasma, fecal metabolome showed the strongest association with the gut microbiome. There are 1073, 191, and 81 statistically significant pairs (P < 0.05) in the correlation analysis for fecal, urine, and plasma metabolome. Fecal metabolites explained the variance of alpha-diversity of the gut microbiome up to 31.1%, while urine and plasma metabolites only explained the variance of alpha-diversity up to 13.5% and 10.6%. Meanwhile, there were more significant differential metabolites in feces than urine and plasma associated with the stroke marker bacteria.

Conclusions

The systematic association analysis between gut microbiome and metabolomics reveals that fecal metabolites show the strongest association with the gut microbiome, followed by urine and plasma. The findings would promote the association study between the gut microbiome and fecal metabolome to explore key factors that are associated with diseases. We also provide a user-friendly web server and a R package to facilitate researchers to conduct the association analysis of gut microbiome and metabolomics.
Record linkage based patient intersection cardinality for rare disease studies using Mainzelliste and secure multi-party computation
Authors: Kussel Tobias , Brenner Torben , Tremper Galina , Schepers Josef , Lablans Martin , Hamacher Kay
Published: October 2022

Background

The low number of patients suffering from any given rare diseases poses a difficult problem for medical research: With the exception of some specialized biobanks and disease registries, potential study participants’ information are disjoint and distributed over many medical institutions. Whenever some of those facilities are in close proximity, a significant overlap of patients can reasonably be expected, further complicating statistical study feasibility assessments and data gathering. Due to the sensitive nature of medical records and identifying data, data transfer and joint computations are often forbidden by law or associated with prohibitive amounts of effort. To alleviate this problem and to support rare disease research, we developed the Mainzelliste Secure EpiLinker (MainSEL) record linkage framework, a secure Multi-Party Computation based application using trusted-third-party-less cryptographic protocols to perform privacy-preserving record linkage with high security guarantees. In this work, we extend MainSEL to allow the record linkage based calculation of the number of common patients between institutions. This allows privacy-preserving statistical feasibility estimations for further analyses and data consolidation. Additionally, we created easy to deploy software packages using microservice containerization and continuous deployment/continuous integration. We performed tests with medical researchers using MainSEL in real-world medical IT environments, using synthetic patient data.

Results

We show that MainSEL achieves practical runtimes, performing 10 000 comparisons in approximately 5 minutes. Our approach proved to be feasible in a wide range of network settings and use cases. The “lessons learned” from the real-world testing show the need to explicitly support and document the usage and deployment for both analysis pipeline integration and researcher driven ad-hoc analysis use cases, thus clarifying the wide applicability of our software. MainSEL is freely available under:https://github.com/medicalinformatics/MainSEL

Conclusions

MainSEL performs well in real-world settings and is a useful tool not only for rare disease research, but medical research in general. It achieves practical runtimes, improved security guarantees compared to existing solutions, and is simple to deploy in strict clinical IT environments. Based on the “lessons learned” from the real-word testing, we hope to enable a wide range of medical researchers to meet their needs and requirements using modern privacy-preserving technologies.
The role of the adaptive immune system and T cell dysfunction in neurodegenerative diseases
Authors: DeMaio Alexa , Mehrotra Shikhar , Sambamurti Kumar , Husain Shahid
Published: October 2022

The adaptive immune system and associated inflammation are vital in surveillance and host protection against internal and external threats, but can secondarily damage host tissues. The central nervous system is immune-privileged and largely protected from the circulating inflammatory pathways. However, T cell involvement and the disruption of the blood–brain barriers have been linked to several neurodegenerative diseases including Parkinson's disease, Alzheimer’s disease, and multiple sclerosis. Under normal physiological conditions, regulatory T cells (Treg cells) dampen the inflammatory response of effector T cells. In the pathological states of many neurodegenerative disorders, the ability of Treg cells to mitigate inflammation is reduced, and a pro-inflammatory environment persists. This perspective review provides current knowledge on the roles of T cell subsets (e.g., effector T cells, Treg cells) in neurodegenerative and ocular diseases, including uveitis, diabetic retinopathy, age-related macular degeneration, and glaucoma. Many neurodegenerative and ocular diseases have been linked to immune dysregulation, but the cellular events and molecular mechanisms involved in such processes remain largely unknown. Moreover, the role of T cells in ocular pathologies remains poorly defined and limited literature is available in this area of research. Adoptive transfer of Treg cells appears to be a vital immunological approach to control ocular pathologies. Similarities in T cell dysfunction seen among non-ocular neurodegenerative diseases suggest that this area of research has a great potential to develop better therapeutic agents for ocular diseases and warrants further studies. Overall, this perspective review article provides significant information on the roles of T cells in numerous ocular and non-ocular neurodegenerative diseases.
The effects of completion of continuum of care in maternal health services on adverse birth outcomes in Northwestern Ethiopia: a prospective follow-up study
Authors: Zelka Muluwas Amentie , Yalew Alemayehu Worku , Debelew Gurmesa Tura
Published: October 2022

Background

Globally, around 4 million babies die within the first month of birth annually with more than 3 million stillbirths. Of them, 99% of newborn deaths and 98% of stillbirths occur in developing countries. Despite giving priority to maternal health services, adverse birth outcomes are still major public health problems in the study area. Hence, a continuum of care (CoC) is a core key strategy to overcome those challenges. The study conducted on the effectiveness of continuum of care in maternal health services was scarce in developing countries and not done in the study area. We aimed to assess the effectiveness of continuum of care and determinants of adverse birth outcomes.

Methods

Community and health facility-linked prospective follow-up study designs were employed from March 2020 to January 2021 in Northwestern Ethiopia. A multistage clustered sampling technique was used to recruit 2198 pregnant women. Data were collected by using a semi-structured and pretested questionnaire. Collected data were coded, entered, cleaned, and analyzed by STATA 14. Multilevel logistic regression model was used to identify community and individual-level factors. Finally, propensity score matching was applied to determine the effectiveness of continuum of care.

Results

The magnitude of adverse birth outcomes was 12.4% (95% CI 12.2–12.7): stillbirth (2.8%; 95% CI 2.7–3.0), neonatal mortality (3.1%; 95% CI 2.9–3.2), and neonatal morbidity (6.8%; 95% CI 6.6–7.0). Risk factors were poor household wealth (AOR = 3.3; 95% CI 1.07–10.23), pregnant-related maternal complications during pregnancy (AOR = 3.29; 95% CI 1.68–6.46), childbirth (AOR = 6.08; 95% CI 2.36–15.48), after childbirth (AOR = 5.24; 95% CI 2.23–12.33), an offensive odor of amniotic fluid (AOR = 3.04; 95% CI 1.37–6.75) and history of stillbirth (AOR = 4.2; 95% CI 1.78–9.93). Whereas, receiving iron-folic acid (AOR = 0.44; 95% CI 0.14–0.98), initiating breastfeeding within 1 h (AOR = 0.22; 95% CI 0.10–0.50) and immunizing newborn (AOR = 0.33; 95% CI 0.12–0.93) were protective factors. As treatment effect, completion of continuum of care via time dimension (β = − 0.03; 95% CI − 0.05, − 0.01) and space dimension (β = − 0.03; 95% CI − 0.04, − 0.01) were significantly reduce perinatal death.

Conclusions

Adverse birth outcomes were high as compared with national targets. Completion of continuum of care is an effective intervention for reducing perinatal death. Efforts should be made to strengthen the continuum of care in maternal health services, iron supplementation, immunizing and early initiation of breastfeeding.
A unilateral robotic knee exoskeleton to assess the role of natural gait assistance in hemiparetic patients
Authors: Lora-Millan Julio Salvador , Sanchez-Cuesta Francisco José , Romero Juan Pablo , Moreno Juan C. , Rocon Eduardo
Published: October 2022

Background

Hemiparetic gait is characterized by strong asymmetries that can severely affect the quality of life of stroke survivors. This type of asymmetry is due to motor deficits in the paretic leg and the resulting compensations in the nonparetic limb. In this study, we aimed to evaluate the effect of actively promoting gait symmetry in hemiparetic patients by assessing the behavior of both paretic and nonparetic lower limbs. This paper introduces the design and validation of the REFLEX prototype, a unilateral active knee–ankle–foot orthosis designed and developed to naturally assist the paretic limbs of hemiparetic patients during gait.

Methods

REFLEX uses an adaptive frequency oscillator to estimate the continuous gait phase of the nonparetic limb. Based on this estimation, the device synchronically assists the paretic leg following two different control strategies: (1) replicating the movement of the nonparetic leg or (2) inducing a healthy gait pattern for the paretic leg. Technical validation of the system was implemented on three healthy subjects, while the effect of the generated assistance was assessed in three stroke patients. The effects of this assistance were evaluated in terms of interlimb symmetry with respect to spatiotemporal gait parameters such as step length or time, as well as the similarity between the joint’s motion in both legs.

Results

Preliminary results proved the feasibility of the REFLEX prototype to assist gait by reinforcing symmetry. They also pointed out that the assistance of the paretic leg resulted in a decrease in the compensatory strategies developed by the nonparetic limb to achieve a functional gait. Notably, better results were attained when the assistance was provided according to a standard healthy pattern, which initially might suppose a lower symmetry but enabled a healthier evolution of the motion of the nonparetic limb.

Conclusions

This work presents the preliminary validation of the REFLEX prototype, a unilateral knee exoskeleton for gait assistance in hemiparetic patients. The experimental results indicate that assisting the paretic leg of a hemiparetic patient based on the movement of their nonparetic leg is a valuable strategy for reducing the compensatory mechanisms developed by the nonparetic limb.
Adhered ECMO cannula in COVID-19 related severe acute respiratory failure
Authors: Kamalia Mohammed A. , Carlson Samuel F. , Melamed Joshua , Ubert Adam , Rossi Peter J. , Durham Lucian A.
Published: October 2022

Background

Crescent cannula adhesion in the setting of COVID-19 respiratory failure requiring extracorporeal membrane oxygenation (ECMO) support is a novel complication. The objective of this case presentation is to highlight this rare complication and to explore potential predisposing factors and our management strategies.

Case presentation

We present the case of a 25 y.o. patient with COVID-19 respiratory failure requiring ECMO support for 16-days in which a 32 Fr crescent cannula became adherent to the SVC and proximal jugular vein. Attempts to remove the cannula at the bedside failed due to immobility of the cannula. Ultrasound of the right neck was unremarkable, so he was taken to the hybrid OR where both TEE and fluoroscopy were unrevealing. An upper sternotomy was performed, and the superior vena cava and proximal jugular vein were dissected revealing a 2 cm segment of the distal SVC and proximal jugular vein that was densely sclerosed and adherent to the cannula. The vessel was opened across the adherent area at the level of the innominate vein and the cannula was then able to be withdrawn. The patient suffered no ill effects and had an unremarkable recovery to discharge.

Conclusions

To date, there have been no reports of crescent cannula adhesion related complications. In patients with COVID-19 respiratory failure requiring ECMO, clinicians should be aware of widespread hypercoagulability and the potential of unprovoked, localized venous sclerosis and cannula adhesion. We report our technique of decannulation in the setting of cannula adhesion and hope that presentation will shed further light on this complication allowing clinicians to optimize patient care.
The Korean undiagnosed diseases program phase I: expansion of the nationwide network and the development of long-term infrastructure
Authors: Kim Soo Yeon , Lee Seungbok , Woo Hyewon , Han Jiyeon , Ko Young Jun , Shim Youngkyu , Park Soojin , Jang Se Song , Lim Byung Chan , Ko Jung Min , Kim Ki Joong , Cho Anna , Kim Hunmin , Hwang Hee , Choi Ji Eun , Kim Man Jin , Moon Jangsup , Seong Moon-Woo , Park Sung Sup , Choi Sun Ah , Lee Ji Eun , Kwon Young Se , Sohn Young Bae , Kim Jon Soo , Kim Won Seop , Lee Yun Jeong , Kwon Soonhak , Kim Young Ok , Kook Hoon , Cho Yong Gon , Cheon Chong Kun , Kang Ki-Soo , Song Mi-Ryoung , Kim Young-Joon , Cha Hyuk-Jin , Choi Hee-Jung , Kee Yun , Park Sung-Gyoo , Baek Seung Tae , Choi Murim , Ryu Dong-Sung , Chae Jong-Hee
Published: October 2022

Background

Phase I of the Korean Undiagnosed Diseases Program (KUDP), performed for 3 years, has been completed. The Phase I program aimed to solve the problem of undiagnosed patients throughout the country and develop infrastructure, including a data management system and functional core laboratory, for long-term translational research. Herein, we share the clinical experiences of the Phase I program and introduce the activities of the functional core laboratory and data management system.

Results

During the program (2018–2020), 458 patients were enrolled and classified into 3 groups according to the following criteria: (I) those with a specific clinical assessment which can be verified by direct testing (32 patients); (II) those with a disease group with genetic and phenotypic heterogeneity (353 patients); and (III) those with atypical presentations or diseases unknown to date (73 patients). All patients underwent individualized diagnostic processes based on the decision of an expert consortium. Confirmative diagnoses were obtained for 242 patients (52.8%). The diagnostic yield was different for each group: 81.3% for Group I, 53.3% for Group II, and 38.4% for Group III. Diagnoses were made by next-generation sequencing for 204 patients (84.3%) and other genetic testing for 35 patients (14.5%). Three patients (1.2%) were diagnosed with nongenetic disorders. The KUDP functional core laboratory, with a group of experts, organized a streamlined research pipeline covering various resources, including animal models, stem cells, structural modeling and metabolic and biochemical approaches. Regular data review was performed to screen for candidate genes among undiagnosed patients, and six different genes were identified for functional research. We also developed a web-based database system that supports clinical cohort management and provides a matchmaker exchange protocol based on a matchbox, likely to reinforce the nationwide clinical network and further international collaboration.

Conclusions

The KUDP evaluated the unmet needs of undiagnosed patients and established infrastructure for a data-sharing system and future functional research. The advancement of the KUDP may lead to sustainable bench-to-bedside research in Korea and contribute to ongoing international collaboration.
Cancer-associated fibroblast-specific lncRNA LINC01614 enhances glutamine uptake in lung adenocarcinoma
Authors: Liu Tongyan , Han Chencheng , Fang Panqi , Ma Zhifei , Wang Xiaoxiao , Chen Hao , Wang Siwei , Meng Fanchen , Wang Cheng , Zhang Erbao , Dong Guozhang , Zhu Hongyu , Yin Wenda , Wang Jie , Zuo Xianglin , Qiu Mantang , Wang Jinke , Qian Xu , Shen Hongbing , Xu Lin , Hu Zhibin , Yin Rong
Published: October 2022

Background

Besides featured glucose consumption, recent studies reveal that cancer cells might prefer “addicting” specific energy substrates from the tumor microenvironment (TME); however, the underlying mechanisms remain unclear.

Methods

Fibroblast-specific long noncoding RNAs were screened using RNA-seq data of our NJLCC cohort, TCGA, and CCLE datasets. The expression and package of LINC01614 into exosomes were identified using flow cytometric sorting, fluorescence in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (RT-PCR). The transfer and functional role of LINC01614 in lung adenocarcinoma (LUAD) and CAFs were investigated using 4-thiouracil-labeled RNA transfer and gain- and loss-of-function approaches. RNA pull-down, RNA immunoprecipitation, dual-luciferase assay, gene expression microarray, and bioinformatics analysis were performed to investigate the underlying mechanisms involved.

Results

We demonstrate that cancer-associated fibroblasts (CAFs) in LUAD primarily enhance the glutamine metabolism of cancer cells. A CAF-specific long noncoding RNA, LINC01614, packaged by CAF-derived exosomes, mediates the enhancement of glutamine uptake in LUAD cells. Mechanistically, LINC01614 directly interacts with ANXA2 and p65 to facilitate the activation of NF-κB, which leads to the upregulation of the glutamine transporters SLC38A2 and SLC7A5 and eventually enhances the glutamine influx of cancer cells. Reciprocally, tumor-derived proinflammatory cytokines upregulate LINC01614 in CAFs, constituting a feedforward loop between CAFs and cancer cells. Blocking exosome-transmitted LINC01614 inhibits glutamine addiction and LUAD growth in vivo. Clinically, LINC01614 expression in CAFs is associated with the glutamine influx and poor prognosis of patients with LUAD.

Conclusion

Our study highlights the therapeutic potential of targeting a CAF-specific lncRNA to inhibit glutamine utilization and cancer progression in LUAD.
Exosomal circZNF451 restrains anti-PD1 treatment in lung adenocarcinoma via polarizing macrophages by complexing with TRIM56 and FXR1
Authors: Gao Jian , Ao Yong-Qiang , Zhang Ling-Xian , Deng Jie , Wang Shuai , Wang Hai-Kun , Jiang Jia-Hao , Ding Jian-Yong
Published: October 2022

Background

Although success was achieved in the therapy for a minority of advanced lung adenocarcinoma (LUAD) patients, anti-programmed death 1 (PD1) resistance was found in most LUAD patients. Here, we aimed to uncover a potential role of exosomal circular RNAs (circRNAs) in LUAD refractory to PD1 blockade. 

Methods

circRNA sequencing and qRT-PCR were performed to determine the level of exosomal circRNAs in LUAD patients subsequently treated with anti-PD1. Then, the RNA pulldown, RNA immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, luciferase reporter assays, flow cytometry, RNA sequencing, and in vitro and in vivo models were used to uncover the biological functions and underlying mechanism of circZNF451 in LUAD anti-PD1 treatment resistance.

Results

circRNA sequencing and qRT-PCR identified the up-regulation of exosomal circZNF451 from LUAD patients with progressive disease (PD) compared to those with partial remission (PR) after PD1 blockade therapy. Furthermore, elevated circZNF451 was revealed to be associated with poor prognosis of LUAD patients. Additionally, exosomal circZNF451 was demonstrated to induce an anti-inflammatory phenotype in macrophages and exhaustion of cytotoxic CD8+ T cells, and enhanced TRIM56-mediated degradation of FXR1 to activate the ELF4–IRF4 pathway in macrophages. By transgenic mice, knockout of ELF4 in macrophages was found to rescue immunotherapy efficacy in tumors with high level of exosomal circZNF451.

Conclusion

Exosomal circZNF451 reshapes the tumor immune microenvironment by inducing macrophages polarization via the FXR1- ELF4–IRF4 axis and is a novel biomarker for predicting the sensitivity of PD1 blockade in LUAD.
Retrospective analysis of GnRH-a prolonged protocol for in vitro fertilization in 18,272 cycles in China
Authors: Tian Lifeng , Xia Leizhen , Wu Qiongfang
Published: October 2022

Background

This large-cohort, retrospective study investigates the relationship between the number of oocytes retrieved and the clinical outcomes for patients receiving the GnRH-a prolonged protocol (mGnRH-a protocol) for fertilization in vitro or intracytoplasmic sperm injection–embryo transfer (IVF/ICSI-ET) treatment.

Results

We categorized 18,272 cycles into three groups by the number of oocytes retrieved (1–8, 9–17, and ≥ 18) during IVF with the GnRH-a prolonged protocol at the Reproductive Medical Center of Jiangxi Maternal and Child Health Hospital from January 2014 to December 2018 (excluding oocyte donation cycles), analyzing the associations among oocyte number and live birth rates (LBRs) or cumulative LBRs (CLBRs), as well as the rate of moderate-to-severe ovarian hyperstimulation syndrome (OHSS). We defined the primary outcome as LBR and the secondary outcome to include the rate of patients at high risk for OHSS. The LBR (with fresh ET) per cycle of oocyte pick-up increased as the number of retrieved oocytes increased from 1 to ~ 8, plateaued between 9 ~ 17, and steadily decreased thereafter. However, the CLBR per cycle continued to increase as the oocyte number increased, as did the incidence of moderate-to-severe OHSS.

Conclusions

Our results show a strong relationship between the number of oocytes retrieved and the CLBR following IVF treatment. The balance between treatment success and the risk of complications, especially OHSS, should be investigated further. We recommend a fresh-ET strategy for the GnRH-a prolonged protocol because the endometrial receptivity in the fresh cycles was better than those in the frozen cycles.
Pan-cancer analysis of cuproptosis regulation patterns and identification of mTOR-target responder in clear cell renal cell carcinoma
Authors: Long Shichao , Wang Ya , Chen Yuqiao , Fang Tianshu , Yao Yuanbing , Fu Kai
Published: October 2022

Background

The mechanism of cuproptosis, a novel copper-induced cell death by regulating tricarboxylic acid cycle (TCA)-related genes, has been reported to regulate oxidative phosphorylation system (OXPHOS) in cancers and can be regarded as potential therapeutic strategies in cancer; however, the characteristics of cuproptosis in pan-cancer have not been elucidated.

Methods

The multi-omics data of The Cancer Genome Atlas were used to evaluate the cuproptosis-associated characteristics across 32 tumor types. A cuproptosis enrichment score (CEScore) was established using a single sample gene enrichment analysis (ssGSEA) in pan-cancer. Spearman correlation analysis was used to identify pathway most associated with CEScore. Lasso-Cox regression was used to screen prognostic genes associated with OXPHOS and further construct a cuproptosis-related prognostic model in clear cell renal cell carcinoma (ccRCC).

Results

We revealed that most cuproptosis-related genes (CRGs) were differentially expressed between tumors and normal tissues, and somatic copy number alterations contributed to their aberrant expression. We established a CEScore index to indicate cuproptosis status which was associated with prognosis in most cancers. The CEScore was negatively correlated with OXPHOS and significantly featured prognosis in ccRCC. The ccRCC patients with high-risk scores show worse survival outcomes and bad clinical benefits of Everolimus (mTOR inhibitor).

Conclusions

Our findings indicate the importance of abnormal CRGs expression in cancers. In addition, identified several prognostic CRGs as potential markers for prognostic distinction and drug response in the specific tumor. These results accelerate the understanding of copper-induced death in tumor progression and provide cuproptosis-associated novel therapeutic strategies.
The effect of an integrated care intervention of multidisciplinary mental health treatment and employment services for trauma-affected refugees: study protocol for a randomised controlled trial
Authors: Bruhn Maja , Laugesen Henriette , Kromann-Larsen Matilde , Trevino Cathrine Selnes , Eplov Lene , Hjorthøj Carsten , Carlsson Jessica
Published: October 2022

Background

The complexity of past trauma and ongoing post-migration stressors challenges the existing mental health treatment for trauma-affected refugees. Therefore, interventions are needed to accommodate these complex challenges in mental health treatment. This study examines the effect of an add-on integrated care intervention compared to treatment as usual (TAU) for trauma-affected refugees in a randomised controlled trial (RCT).

Methods

The study is carried out at a Danish outpatient clinic and will include 197 treatment-seeking refugees with post-traumatic stress disorder (PTSD) who are unemployed and affiliated with municipal employment services. Mental health TAU comprises 10 sessions with a medical doctor (pharmacological treatment and psychoeducation) and 16–20 sessions with a psychologist (manual-based cognitive behavioural therapy) for a period of 8 to 12 months. The add-on intervention strengthens coordination between mental health treatment and employment interventions with three cross-sectoral collaborative meetings during the mental health treatment. The integrated care intervention draws attention to the bidirectional impact of mental health problems and post-migration stressors and focuses on cross-sectoral shared plans. The primary outcome is functioning, measured by WHODAS 2.0, the interviewer-administered 12-item version, with secondary outcomes measuring quality of life, mental health symptoms, and post-migration stressors.

Discussion

The RCT is novel in intervention design for trauma-affected refugees and will bring forward new perspectives and knowledge of integrated care interventions for trauma-affected refugees. The integrated care intervention is expected to reduce post-migration stressors that negatively affect the treatment of trauma-related mental health problems, thereby improving preconditions for enhanced treatment outcomes. The intervention builds on existing practices in the Danish healthcare and employment sectors, which ensures high scalability and sustainability for future practices.

Trial registration

ClinicalTrials.gov Identifier: NCT04244864, registered 28 January 2020. Protocol version: 17 September 2022, version 2.