bluuebunny/crossref_metadata_2025 huggingface dataset:
CERCAM is a prognostic biomarker associated with immune infiltration of macrophage M2 polarization in head and neck squamous carcinoma
Authors: Yang Ying , Yan Cong , Chen Xiao-Jian
Published: October 2023

Purpose

This study aimed to investigate the relevance of cerebral endothelial cell adhesion molecule (CERCAM) expression to head and neck squamous cell carcinoma (HNSCC) prognosis and immune infiltration by macrophage M2 polarization.

Methods

Timer, UALCAN and HPA databases was used to analyze the differences in mRNA and protein levels of CERCAM expression in HNSCC. The Timer database was also applied to analyze the correlation between CERCAM in HNSCC and immune infiltration. TCGA-HNSCC database was applied to analyze the correlation between CERCAM expression levels and clinicopathological features, and its diagnostic and prognostic value in HNSCC was also assessed. The cBioPortal and MethSurv databases were then applied to analyze the genetic variation and methylation status of CERCAM. In vitro cellular assays were performed to provide evidence that CERCAM promotes malignant biological behavior of tumors and promotes macrophage M2 polarization in tumors. Finally, underlying pathophysiological mechanisms of CERCAM involvement in the development of HNSCC were predicted using a bioinformatics approach.

Results

CERCAM is significantly overexpressed in HNSCC and correlates with poor prognostic levels and has good performance in predicting survival status in HNSCC patients. Cox regression analysis indicates that CERCAM expression levels are independent risk factors for predicting OS, DSS, and PFI. CERCAM promotes tumor malignant biological behavior and promotes macrophage M2 polarization immune infiltration in HNSCC. In addition, CERCAM promotes tumor cell adhesion in head and neck squamous carcinoma and promotes tumor progression through several oncogenic signaling pathways.

Conclusion

CERCAM may serve as a new diagnostic and prognostic biomarker in HNSCC and is a promising therapeutic target for HNSCC.
Caries experience and risk indicators of having decayed teeth among 65-year-olds in Oslo, Norway: a cross-sectional study
Authors: Diep My Tien , Skudutyte-Rysstad Rasa , Sødal Anne Thea Tveit , Young Alix , Hove Lene Hystad
Published: October 2023

Background

Meeting the oral health needs of the increasing population of older adults presents a major challenge in dental care. Knowledge about the oral health status in the young-elderly age group is essential for the planning of future oral health education and prevention programs. The aims of the present study were therefore to investigate the caries experience among 65-year-olds in Oslo, Norway, and to explore associations between having decayed teeth and sociodemographic, behavioural, and biological factors.

Methods

A random sample of 65‑year‑olds in Oslo answered a questionnaire and underwent clinical and radiographic examinations (n = 457, 52% men and 48% women) at the Research Clinic, Faculty of Dentistry, University of Oslo, between February and December 2019. Primary- and secondary coronal and root caries lesions, root remnants, and missing and restored teeth were recorded. Decayed teeth (DT) were defined as teeth with coronal- and root caries lesions that had progressed into dentine and root remnants, and the DMFT/S scores were calculated.

Results

The mean number of teeth was 25 (SD: 4) and the mean DMFT was 19.4 (SD: 4.7). Thirty seven percent of the individuals had at least one decayed tooth (DT > 0), and the mean number of filled teeth (FT) was 16.1 (SD: 5.4). Multivariable logistic regression analysis showed that male gender (OR: 1.8, 95% CI: 1.2–2.8), basic level of education (OR: 1.9, 95% CI: 1.2–2.9), irregular dental attendance (OR: 2.2, 95% CI: 1.0-4.8), and hyposalivation (OR: 2.1, 95% CI: 1.0-4.4) were significant risk indicators for having decayed teeth (DT > 0) (p < 0.05).

Conclusions

In conclusion, 65-year-olds in Oslo had a low average number of decayed and missing teeth, and a high number of restored teeth. Irregular dental attendance and hyposalivation were the strongest risk indicators for having decayed teeth. Based on the present results, it will be important to ensure access to regular dental care and to increase the emphasis on caries preventive measures for individuals with hyposalivation in this age group.
Public attitudes towards genomic data sharing: results from a provincial online survey in Canada
Authors: Etchegary Holly , Darmonkov Georgia , Simmonds Charlene , Pullman Daryl , Rahman Proton
Published: October 2023

Background

While genomic data sharing can facilitate important health research and discovery benefits, these must be balanced against potential privacy risks and harms to individuals. Understanding public attitudes and perspectives on data sharing is important given these potential risks and to inform genomic research and policy that aligns with public preferences and needs.

Methods

A cross sectional online survey measured attitudes towards genomic data sharing among members of the general public in an Eastern Canadian province.

Results

Results showed a moderate comfort level with sharing genomic data, usually into restricted scientific databases with controlled access. Much lower comfort levels were observed for sharing data into open or publicly accessible databases. While respondents largely approved of sharing genomic data for health research permitted by a research ethics board, many general public members were concerned with who would have access to their data, with higher rates of approval for access from clinical or academic actors, but much more limited approval of access from commercial entities or governments. Prior knowledge about sequencing and about research ethics boards were both related to data sharing attitudes.

Conclusions

With evolving regulations and guidelines for genomics research and data sharing, it is important to consider the perspectives of participants most impacted by these changes. Participant information materials and informed consent documents must be explicit about the safeguards in place to protect genomic data and the policies governing the sharing of data. Increased public awareness of the role of research ethics boards and of the need for genomic data sharing more broadly is also needed.
Analysis of protein secretion in Bacillus subtilis by combining a secretion stress biosensor strain with an in vivo split GFP assay
Authors: Lenz Patrick , Bakkes Patrick J. , Müller Carolin , Malek Marzena , Freudl Roland , Oldiges Marco , Drepper Thomas , Jaeger Karl-Erich , Knapp Andreas
Published: October 2023

Background

Bacillus subtilis is one of the workhorses in industrial biotechnology and well known for its secretion potential. Efficient secretion of recombinant proteins still requires extensive optimization campaigns and screening with activity-based methods. However, not every protein can be detected by activity-based screening. We therefore developed a combined online monitoring system, consisting of an in vivo split GFP assay for activity-independent target detection and an mCherry-based secretion stress biosensor. The split GFP assay is based on the fusion of a target protein to the eleventh β-sheet of sfGFP, which can complement a truncated sfGFP that lacks this β-sheet named GFP1-10. The secretion stress biosensor makes use of the CssRS two component quality control system, which upregulates expression of mCherry in the htrA locus thereby allowing a fluorescence readout of secretion stress.

Results

The biosensor strain B. subtilis PAL5 was successfully constructed by exchanging the protease encoding gene htrA with mCherry via CRISPR/Cas9. The Fusarium solani pisi cutinase Cut fused to the GFP11 tag (Cut11) was used as a model enzyme to determine the stress response upon secretion mediated by signal peptides SPPel, SPEpr and SPBsn obtained from naturally secreted proteins of B. subtilis. An in vivo split GFP assay was developed, where purified GFP1-10 is added to the culture broth. By combining both methods, an activity-independent high-throughput method was created, that allowed optimization of Cut11 secretion. Using the split GFP-based detection assay, we demonstrated a good correlation between the amount of secreted cutinase and the enzymatic activity. Additionally, we screened a signal peptide library and identified new signal peptide variants that led to improved secretion while maintaining low stress levels.

Conclusion

Our results demonstrate that the combination of a split GFP-based detection assay for secreted proteins with a secretion stress biosensor strain enables both, online detection of extracellular target proteins and identification of bottlenecks during protein secretion in B. subtilis. In general, the system described here will also enable to monitor the secretion stress response provoked by using inducible promoters governing the expression of different enzymes.
An injectable and thermosensitive hydrogel with nano-aided NIR-II phototherapeutic and chemical effects for periodontal antibacteria and bone regeneration
Authors: Wang Weixiang , Zhang Guorong , Wang Yanyi , Ran Jianchuan , Chen Lin , Wei Zheng , Zou Huihui , Cai Yu , Han Wei
Published: October 2023

Periodontitis is a common public health problem worldwide and an inflammatory disease with irregular defect of alveolar bone caused by periodontal pathogens. Both antibacterial therapy and bone regeneration are of great importance in the treatment of periodontitis. In this study, injectable and thermosensitive hydrogels with 3D networks were used as carriers for controlled release of osteo-inductive agent (BMP-2) and Near Infrared Region-II (NIR-II) phototherapy agents (T8IC nano-particles). T8IC nano-particles were prepared by reprecipitation and acted as photosensitizer under 808 nm laser irradiation. Besides, we promoted photodynamic therapy (PDT) through adding H2O2 to facilitate the antibacterial effect instead of increasing the temperature of photothermal therapy (PTT). Hydrogel + T8IC + Laser + BMP-2 + H2O2 incorporated with mild PTT (45 °C), enhanced PDT and sustained release of BMP-2. It was present with excellent bactericidal effect, osteogenic induction and biosafety both in vitro and in vivo. Besides, immunohistochemistry staining and micro-CT analyses had confirmed that PTT and PDT could promote bone regeneration through alleviating inflammation state. Altogether, this novel approach with synergistic antibacterial effect, anti-inflammation and bone regeneration has a great potential for the treatment of periodontitis in the future.
Real-time detection of laryngopharyngeal cancer using an artificial intelligence-assisted system with multimodal data
Authors: Li Yun , Gu Wenxin , Yue Huijun , Lei Guoqing , Guo Wenbin , Wen Yihui , Tang Haocheng , Luo Xin , Tu Wenjuan , Ye Jin , Hong Ruomei , Cai Qian , Gu Qingyu , Liu Tianrun , Miao Beiping , Wang Ruxin , Ren Jiangtao , Lei Wenbin
Published: October 2023

Background

Laryngopharyngeal cancer (LPC) includes laryngeal and hypopharyngeal cancer, whose early diagnosis can significantly improve the prognosis and quality of life of patients. Pathological biopsy of suspicious cancerous tissue under the guidance of laryngoscopy is the gold standard for diagnosing LPC. However, this subjective examination largely depends on the skills and experience of laryngologists, which increases the possibility of missed diagnoses and repeated unnecessary biopsies. We aimed to develop and validate a deep convolutional neural network-based Laryngopharyngeal Artificial Intelligence Diagnostic System (LPAIDS) for real-time automatically identifying LPC in both laryngoscopy white-light imaging (WLI) and narrow-band imaging (NBI) images to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists.

Methods

All 31,543 laryngoscopic images from 2382 patients were categorised into training, verification, and test sets to develop, validate, and internal test LPAIDS. Another 25,063 images from five other hospitals were used as external tests. Overall, 551 videos were used to evaluate the real-time performance of the system, and 200 randomly selected videos were used to compare the diagnostic performance of the LPAIDS with that of laryngologists. Two deep-learning models using either WLI (model W) or NBI (model N) images were constructed to compare with LPAIDS.

Results

LPAIDS had a higher diagnostic performance than models W and N, with accuracies of 0·956 and 0·949 in the internal image and video tests, respectively. The robustness and stability of LPAIDS were validated in external sets with the area under the receiver operating characteristic curve values of 0·965–0·987. In the laryngologist-machine competition, LPAIDS achieved an accuracy of 0·940, which was comparable to expert laryngologists and outperformed other laryngologists with varying qualifications.

Conclusions

LPAIDS provided high accuracy and stability in detecting LPC in real-time, which showed great potential for using LPAIDS to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists.
Stabilizing histamine release in gut mast cells mitigates peripheral and central inflammation after stroke
Authors: Conesa Maria P. Blasco , Blixt Frank W. , Peesh Pedram , Khan Romeesa , Korf Janelle , Lee Juneyoung , Jagadeesan Gayathri , Andersohn Alexander , Das Tushar K. , Tan Chunfeng , Di Gesu Claudia , Colpo Gabriela Delevati , Moruno-Manchón Jose Félix , McCullough Louise D. , Bryan Robert , Ganesh Bhanu P.
Published: October 2023

Stroke is the most common cause of long-term disability and places a high economic burden on the global healthcare system. Functional outcomes from stroke are largely determined by the extent of ischemic injury, however, there is growing recognition that systemic inflammatory responses also contribute to outcomes. Mast cells (MCs) rapidly respond to injury and release histamine (HA), a pro-inflammatory neurotransmitter that enhances inflammation. The gut serves as a major reservoir of HA. We hypothesized that cromolyn, a mast cell stabilizer that prevents the release of inflammatory mediators, would decrease peripheral and central inflammation, reduce MC trafficking to the brain, and improve stroke outcomes. We used the transient middle cerebral artery occlusion (MCAO) model of ischemic stroke in aged (18 mo) male mice to investigate the role of MC in neuroinflammation post-stroke. After MCAO we treated mice with 25 mg/kg body weight of cromolyn (MC stabilizer) by oral gavage. Cromolyn was administered at 3 h, 10 h, 24 h and every 24 h for 3 days post-stroke. Three control groups were used. One group underwent a sham surgery and was treated with cromolyn, one received sham surgery with PBS vehicle and the third underwent MCAO with PBS vehicle. Mice were euthanized at 24 h and 3 days post-stroke. Cromolyn administration significantly reduced MC numbers in the brain at both 24 h and 3 days post-stroke. Infarct volume was not significantly different between groups, however improved functional outcomes were seen at 3 days post-stroke in mice that received cromolyn. Treatment with cromolyn reduced plasma histamine and IL-6 levels in both the 24-h and 3-day cohorts. Gut MCs numbers were significantly reduced after cromolyn treatment at 24 h and 3 days after stroke. To determine if MC trafficking from the gut to the brain occurred after injury, GFP+MCs were adoptively transferred to c-kit−/− MC knock-out animals prior to MCAO. 24 h after stroke, elevated MC recruitment was seen in the ischemic brain. Preventing MC histamine release by cromolyn improved gut barrier integrity and an improvement in stroke-induced dysbiosis was seen with treatment. Our results show that preventing MC histamine release possesses prevents post-stroke neuroinflammation and improves neurological and functional outcomes.

Graphical abstract
Early selection of carrot somatic hybrids: a promising tool for species with high regenerative ability
Authors: Mackowska Katarzyna , Stelmach-Wityk Katarzyna , Grzebelus Ewa
Published: October 2023

Background

Since its discovery, somatic hybridization has been used to overcome the sexual barriers between cultivated and wild species. A combination of two somatic cells might provide a novel set of features, often of agronomical importance. Here, we report a successful approach for production and selection of interspecific somatic hybrid plants between cultivated and wild carrot using dual-labelling of protoplasts and an early selection of fused cells via micromanipulator. Both subspecies used in this study are characterised by a very high regenerative ability in protoplast cultures. Thus, a precise and effective method of hybrid selection is essential to assure the development and regeneration of much less numerous heterokaryons in the post-fusion cell mixture.

Results

Electrofusion parameters, such as alternating current and direct current, were optimised for an efficient alignment of protoplasts and reversible membrane breakdown followed by a cell fusion. Four hundred twenty-nine cells emitting green–red fluorescence, identified as hybrids, were obtained. Co-culture with donor-derived protoplasts in the alginate feeder layer system stimulated re-synthesis of the cell wall and promoted cell divisions of fusants. Somatic embryogenesis occurred in hybrid-derived microcalli cultures, followed by plant regeneration. Regenerated hybrids produced yellowish storage roots and leaves of an intermediate shape between cultivated and wild subspecies. The intron length polymorphism analysis revealed that 123 of 124 regenerated plants were hybrids.

Conclusions

The developed protocol for protoplast fusion and an early selection of hybrids may serve as an alternative to combining genomes and transferring nuclear or cytoplasmatic traits from wild Daucus species to cultivated carrot.
The correlation between the lumbar disc MRI high-intensity zone and discogenic low back pain: a systematic review and meta-analysis
Authors: Yang Lei , Li Wenhao , Yang Yongdong , Zhao He , Yu Xing
Published: October 2023

Objective

This study aimed to investigate the correlation between the MRI high-intensity zone (HIZ) and the pathogenesis of discogenic low back pain.

Methods

Literature from PubMed, EMBASE, Cochrane Library, Science Direct, China Knowledge Network, Wanfang Database, and China Biomedical Literature Database was searched until August 2023. Cohort studies including patients with low back pain who underwent lumbar spine MRI and discography, as well as the results evaluating the correlation between HIZ and discography for morphological changes in the disc and pain replication phenomena, were included in the analysis. The literature that met the inclusion criteria was screened, and the methodological quality of the included studies was evaluated. Meta-analysis of the extracted data was performed by using RevMan 5.1.1.

Results

In total, 28 reports were included in this meta-analysis. There was a statistically significant correlation between a positive HIZ and abnormal disc morphology in discography (OR 28.15, 95% CI [7.38, 107.46], p < 0.00001). Patients with HIZ-positive discs had a significantly higher incidence of consistent pain (71.0%, 969/1365) than those with HIZ-negative imaging (29.0%, 1314/4524) (OR 7.71, 95% CI [5.29, 11.23], p < 0.00001).Segments that were HIZ-positive and had abnormal disc morphology had a higher incidence of consistent pain (86.1%, 230/267) than HIZ-negative subjects (32.2%, 75/233) (OR 14.09, 95% CI [2.12, 93.48], p = 0.006).

Conclusion

A positive MRI T2-weighted image of the lumbar disc with HIZ indicates disc degeneration. In addition, HIZ may be a specific indicator for the physical diagnosis of discogenic low back pain. A more advanced degree of disc degeneration on the basis of HIZ positivity corresponded to a greater probability of discography-induced consistent pain, whereas the degree of disc degeneration on the basis of HIZ negativity was less correlated with contrast-induced consistent pain.
Analysis of the predictive value of the Geriatric Nutritional Risk Index for osteoporosis in elderly patients with T2DM: a single-center retrospective study
Authors: Sun Silu , Tao Simin , Xi Xiaoyan , Jiang Tao , Zhu Qian , Zhou Yan , Li Hui
Published: October 2023

Background

Malnutrition is recognized as a risk factor for osteoporosis and T2DM. Previous studies have demonstrated the relationship between nutritional assessment tools and BMD. However, few studies have compared the effects of three nutritional risk assessment tools (GNRI, CONUT, and PNI). This study aimed to investigate the correlation between three nutritional assessment tools and BMD and to compare their validity in predicting osteoporosis in type 2 diabetes mellitus in the elderly.

Methods

This retrospective study collected clinical data from 525 elderly patients with type 2 diabetes mellitus and categorized the patients into osteoporotic and non-osteoporotic groups. The correlation between the three nutritional assessment tools and BMD was analyzed using Spearman partial correlation. Binary logistics regression was used to analyze the relationship between GNRI and osteoporosis. ROC curves were used to compare the validity of GNRI, PNI, and CONUT in predicting osteoporosis.

Results

Spearman’s partial correlation showed a positive correlation between femoral neck BMD and lumbar spine BMD, but no correlation was observed between total hip BMD and GNRI. Logistic regression analyses showed no association between PNI, CONUT scores, and the development of osteoporosis. After adjusting for age, sex, smoking, alcohol consumption, BMI, ALB, Cr, UA, FBG, TG, and HDL, the correlation between GNRI and osteoporosis remained. ROC curve analysis showed that GNRI in combination with age and albumin had better predictive ability for osteoporosis than PNI and CONUT.

Conclusion

GNRI was an independent protective factor against osteoporosis in elderly patients with T2DM, and the predictive ability of GNRI for osteoporosis in elderly patients with T2DM was better than that of PNI and CONUT scores.
Association between ankylosing spondylitis and m6A methylation
Authors: Luan Zhiwei , Wang Yansong
Published: October 2023

Background

N6-methyl adenosine (m6A) is the most common reversible mRNA modification in eukaryotes implicated in key roles in various biological processes. The purpose of our analysis was to examine the association of ankylosing spondylitis (AS) with m6A methylation.

Method

We obtained 72 samples from the data set GSE73754, including 52 AS patients and 20 healthy people. We divided the samples into two groups: the experimental group and the control group, and then observed the differences of 26 m6A related genes in the two groups. We also analyzed the correlation between different m6A genes. We used a random forest tree model to screen seven m6A signature genes associated with AS to evaluate its prevalence. Next, the samples were classified according to the m6a content and differential genes. Immune analysis, gene ontology, and KEGG enrichment analyses were performed. Finally, we scored each sample with m6a and analyzed the relationship between different samples and inflammation-related factors.

Results and conclusion

In conclusion, we screened out AS-related genes and the nomogram showed that they were negatively correlated with the incidence of AS. And we found that AS may have some relationship with immunity. Our analysis results could provide further insights into the treatment of AS.
What is the stable internal fixation for the unstable and osteoporotic supracondylar femoral fractures: a finite element analysis
Authors: Rao Jianwei , Zhang Junchao , Ye Zhou , Zhang Liguang , Xu Jiangbao
Published: October 2023

Background

Osteoporotic supracondylar femoral fractures (OSFF) have historically been managed by the lateral anatomical locking plate with reasonable success. However, for some kinds of unstable and osteoporotic supracondylar femoral fractures (UOSFF), especially with bone defects, unilateral locking plate (ULLP) fixation failed or resulted in implant breakage. This paper is going to explore what is the stable internal fixation for UOSFF by adding the bilateral locking plate (BLLP) fixation.

Methods

OSFF models were divided into two groups according to the fracture line type, which would be further subdivided according to their angle of fracture line, presence of bone defect, location, and degree of bone defect. Thereafter, kinds of locking plate fixation were constructed. A 2010-N load was applied to the femoral head, and a 1086-N load was applied to the greater trochanter. In this condition, the maximum von Mises stress distribution of models were investigated.

Results

Firstly, it was obviously found that the stress concentration in the BLLP group was more dispersed than that in the ULLP group. Secondly, according to the fracture line analysis, the stress value of fracture line type in “\” model group was higher than that of “/” model group. Moreover, with the increase in fracture line angle, the stress value of the model increased. Thirdly, from the bone defect analysis, the stress value of the medial bone defect (MBD) model group was higher than that of the lateral bone defect (LBD) model group. And as the degree of bone defect increased, the stress value increased gradually in the model group.

Conclusion

In the following four cases, lateral unilateral locking plate fixation cannot effectively stabilize the fracture end, and double locking plate internal fixation is a necessary choice. First, when the angle of the fracture line is large (30, 45). Second, when the fracture line type is “/.” Third, when the bone defect is large. Fourth, when the bone defect is medial.
Successful conservative treatment for left ventricular free wall rupture after acute myocardial infarction
Authors: Kinoshita Haruyuki , Kanegawa Munehiro , Morita Masashi , Maeda Shiori , Sumimoto Yoji , Masada Kenji , Shimonaga Takashi , Hiraoka Toshifumi , Imai Katsuhiko , Sugino Hiroshi
Published: October 2023

Left ventricular free wall rupture (LVFWR) is a rare but fatal complication of acute myocardial infarction (AMI). An 81-year-old female patient with several cardiovascular risk factors presented to the emergency department with symptoms of developing a chronic stomachache and cold sweat. An echocardiograph showed wall motion abnormalities from the lateral to posterior wall, as well as pericardial effusion containing clots of up to 17 mm in the posterior wall that indicated LVFWR after AMI. Although she was conscious after being brought to the initial care unit, she suddenly lost consciousness and fell into electromechanical dissociation (EMD). Endotracheal intubation was immediately initiated and her pericardial drainage and intra aortic balloon pump (IABP) placement, and hemodynamics recovered. Although she had 100% obstruction in the left circumflex artery (LCX) #12 on coronary angiography (CAG), she was discharged to the Intensive Care Unit (ICU) without percutaneous coronary intervention (PCI). Conservative treatment such as intubation, sedation, pericardiocentesis and strict blood pressure management as well as treatment by IABP long-term support led to the patient being uneventfully discharged after 60 days.
Transcatheter aortic valve replacement 23 years after heart transplant for aortic insufficiency
Authors: Jones Andrew , Amirjamshidi Hossein , Olverson George , Ling Frederick S. , Hisamoto Kazuhiro
Published: October 2023

Background

Clinicians continue to expand the availability of transcatheter aortic valve replacement (TAVR) for patients who historically would have been ineligible for surgical aortic valve replacement. Historically, reoperative aortic valve surgery after transplant was immensely complicated and high risk due to the repeat sternotomy approach, and the immunosuppression in transplant patients. As heart transplant patients continue to live longer, patients are beginning to develop novo aortic pathology of the transplanted organ. In these patients, TAVR may be a valuable rescue therapy for those with de-novo aortic valve disease.

Case presentation

Here, we present a single case of a 70-year-old man with a history of heart transplant 23 years prior complicated by severe sternal infection and subsequent removal of his sternum. Additionally, this patient had a recent history of kidney transplant due to renal cell carcinoma necessitating nephrectomy. He subsequently developed progressive symptomatic aortic insufficiency and underwent a successful TAVR to treat his new aortic disease.

Conclusions

To our knowledge, this represents only the second case report of TAVR for severe aortic insufficiency and one of the first reports of TAVR in a multiple organ recipient. TAVR may represent an important rescue therapy for post-transplant valve pathologies instead of high-risk reoperative surgical aortic valve replacement.
Challenges in the care of individuals with severe primary insulin-like growth factor-I deficiency (SPIGFD): an international, multi-stakeholder perspective
Authors: Backeljauw Philippe F. , Andrews Mary , Bang Peter , Dalle Molle Leo , Deal Cheri L. , Harvey Jamie , Langham Shirley , Petriczko Elżbieta , Polak Michel , Storr Helen L. , Dattani Mehul T.
Published: October 2023

Background

Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care.

Objective

To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally.

Methods

An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD.

Results

As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing.

Conclusions

To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care.

Medical writing support was industry-sponsored.
Comparative analysis of response to treatments and molecular features of tumor-derived organoids versus cell lines and PDX derived from the same ovarian clear cell carcinoma
Authors: Thorel Lucie , Morice Pierre-Marie , Paysant Hippolyte , Florent Romane , Babin Guillaume , Thomine Cécilia , Perréard Marion , Abeilard Edwige , Giffard Florence , Brotin Emilie , Denoyelle Christophe , Villenet Céline , Sebda Shéhérazade , Briand Mélanie , Joly Florence , Dolivet Enora , Goux Didier , Blanc-Fournier Cécile , Jeanne Corinne , Villedieu Marie , Meryet-Figuiere Matthieu , Figeac Martin , Poulain Laurent , Weiswald Louis-Bastien
Published: October 2023

Background

In the era of personalized medicine, the establishment of preclinical models of cancer that faithfully recapitulate original tumors is essential to potentially guide clinical decisions.

Methods

We established 7 models [4 cell lines, 2 Patient-Derived Tumor Organoids (PDTO) and 1 Patient-Derived Xenograft (PDX)], all derived from the same Ovarian Clear Cell Carcinoma (OCCC). To determine the relevance of each of these models, comprehensive characterization was performed based on morphological, histological, and transcriptomic analyses as well as on the evaluation of their response to the treatments received by the patient. These results were compared to the clinical data.

Results

Only the PDX and PDTO models derived from the patient tumor were able to recapitulate the patient tumor heterogeneity. The patient was refractory to carboplatin, doxorubicin and gemcitabine, while tumor cell lines were sensitive to these treatments. In contrast, PDX and PDTO models displayed resistance to the 3 drugs. The transcriptomic analysis was consistent with these results since the models recapitulating faithfully the clinical response grouped together away from the other classical 2D cell culture models. We next investigated the potential of drugs that have not been used in the patient clinical management and we identified the HDAC inhibitor belinostat as a potential effective treatment based on PDTO response.

Conclusions

PDX and PDTO appear to be the most relevant models, but only PDTO seem to present all the necessary prerequisites for predictive purposes and could constitute relevant tools for therapeutic decision support in the context of these particularly aggressive cancers refractory to conventional treatments.
Anoikis resistance and immune escape mediated by Epstein-Barr virus-encoded latent membrane protein 1-induced stabilization of PGC-1α promotes invasion and metastasis of nasopharyngeal carcinoma
Authors: Liao Chaoliang , Li Min , Chen Xue , Tang Chenpeng , Quan Jing , Bode Ann M. , Cao Ya , Luo Xiangjian
Published: October 2023

Background

Epstein-Barr virus (EBV) is the first discovered human tumor virus that is associated with a variety of malignancies of both lymphoid and epithelial origin including nasopharyngeal carcinoma (NPC). The EBV-encoded latent membrane protein 1 (LMP1) has been well-defined as a potent oncogenic protein, which is intimately correlated with NPC pathogenesis. Anoikis is considered to be a physiological barrier to metastasis, and avoiding anoikis is a major hallmark of metastasis. However, the role of LMP1 in anoikis-resistance and metastasis of NPC has not been fully identified.

Methods

Trypan blue staining, colony formation assay, flow cytometry, and TUNEL staining, as well as the detection of apoptosis and anoikis resistance‐related markers was applied to evaluate the anoikis-resistant capability of NPC cells cultured in ultra-low adhesion condition. Co-immunoprecipitation (Co-IP) experiment was performed to determine the interaction among LMP1, PRMT1 and PGC-1α. Ex vivo ubiquitination assay was used to detect the ubiquitination level of PGC-1α. Anoikis- resistant LMP1-positive NPC cell lines were established and applied for the xenograft and metastatic animal experiments.

Results

Our current findings reveal the role of LMP1-stabilized peroxisome proliferator activated receptor coactivator-1a (PGC-1α) in anoikis resistance and immune escape to support the invasion and metastasis of NPC. Mechanistically, LMP1 enhances PGC-1α protein stability by promoting the interaction between arginine methyltransferase 1 (PRMT1) and PGC-1α to elevate the methylation modification of PGC-1α, thus endowing NPC cells with anoikis-resistance. Meanwhile, PGC-1α mediates the immune escape induced by LMP1 by coactivating with STAT3 to transcriptionally up-regulate PD-L1 expression.

Conclusion

Our work provides insights into how virus-encoded proteins recruit and interact with host regulatory elements to facilitate the malignant progression of NPC. Therefore, targeting PGC-1α or PRMT1-PGC-1α interaction might be exploited for therapeutic gain for EBV-associated malignancies.
Accuracy of Pancreatic Stone Protein for diagnosis of sepsis in children admitted to pediatric intensive care or high-dependency care: a pilot study
Authors: Bottari Gabriella , Caruso Mariangela , Paionni Emanuel , De Luca Maia , Romani Lorenza , Pisani Mara , Grandin Annalisa , Gargiullo Livia , Zampini Giorgio , Gagliardi Chiara , Fegatelli Danilo Alunni , Vestri Annarita , Lancella Laura , Porzio Ottavia , Muda Andrea Onetti , Villani Alberto , Atti Marta Ciofi Degli , Raponi Massimiliano , Cecchetti Corrado
Published: October 2023

Background

Pancreatic Stone Protein (PSP) is one of the most promising diagnostic and prognostic markers. The aim of the study was to assess the accuracy of PSP, compared to C-Reactive Protein (CRP), and Procalcitonin (PCT) for sepsis diagnosis in pediatric patients. Furthermore, we explored the correlation of PSP levels with sepsis severity and organ failure measured with PELOD-2 score.

Methods

Forty pediatric patients were enrolled following admission to pediatric intensive care, high dependency care or pediatric ward. PSP blood levels were measured in Emergency Department (nanofluidic point-of-care immunoassay; abioSCOPE, Abionic SA, Switzerland) on day 1, 2, 3, 5 and 7 from the onset of the clinical signs and symptoms of sepsis or SIRS. Inclusion criteria were: 1) patient age (1 month to 18 years old), 2) signs and symptoms of SIRS, irrespective of association with organ dysfunction. Exclusion criteria were: 1) hemato-oncological diseases and/or immunodeficiencies, 2) pancreatic diseases.

Results

Septic patients showed higher PSP levels than those with non-infectious systemic inflammation. The optimal cut-off in diagnosis of sepsis for PSP at day 1 was 167 ng/ml resulted in a sensitivity of 59% (95% IC 36%—79%) and a specificity of 83% (95% IC 58%-96%) with an AUC of 0.636 for PSP in comparison to AUC of 0.722 for PCT and 0.503 for C-RP. ROC analysis for outcome (survival versus no survival) has showed AUC 0.814 for PSP; AUC 0.814 for PCT; AUC of 0.657 for C-RP.

Conclusions

PSP could distinguish sepsis from non-infectious systemic inflammation; however, our results need to be confirmed in larger pediatric population.
Cerebral oximetry monitoring versus usual care for extremely preterm infants: a study protocol for the 2-year follow-up of the SafeBoosC-III randomised clinical trial
Authors: Rasmussen Marie Isabel , Hansen Mathias Lühr , Pellicer Adelina , Gluud Christian , Dempsey Eugene , Mintzer Jonathan , Hyttel-Sørensen Simon , Heuchan Anne Marie , Hagmann Cornelia , Ergenekon Ebru , Dimitriou Gabriel , Pichler Gerhard , Naulaers Gunnar , Cheng Guoqiang , Tkaczyk Jakub , Fuchs Hans , Fumagalli Monica , Nesargi Saudamini , Fredly Siv , Szczapa Tomasz , Plomgaard Anne Mette , Hansen Bo Mølholm , Jakobsen Janus Christian , Greisen Gorm
Published: October 2023

Background

In the SafeBoosC-III trial, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth did not reduce the incidence of death or severe brain injury in extremely preterm infants at 36 weeks’ postmenstrual age, as compared with usual care. Despite an association between severe brain injury diagnosed in the neonatal period and later neurodevelopmental disability, this relationship is not always strong. The objective of the SafeBoosC-III follow-up study is to assess mortality, neurodevelopmental disability, or any harm in trial participants at 2 years of corrected age. One important challenge is the lack of funding for local costs for a trial-specific assessment.

Methods

Of the 1601 infants randomised in the SafeBoosC-III trial, 1276 infants were alive at 36 weeks’ postmenstrual age and will potentially be available for the 2-year follow-up. Inclusion criteria will be enrollment in a neonatal intensive care unit taking part in the follow-up study and parental consent if required by local regulations. We aim to collect data from routine follow-up programmes between the ages of 18 and 30 months of corrected age. If no routine follow-up has been conducted, we will collect informal assessments from other health care records from the age of at least 12 months. A local co-investigator blinded to group allocation will classify outcomes based on these records. We will supplement this with parental questionnaires including the Parent Report of Children’s Abilities—Revised. There will be two co-primary outcomes: the composite of death or moderate or severe neurodevelopmental disability and mean Bayley-III/IV cognitive score. We will use a 3-tier model for prioritisation, based on the quality of data. This approach has been chosen to minimise loss to follow-up assuming that little data is better than no data at all.

Discussion

Follow-up at the age of 2 years is important for intervention trials in the newborn period as only time can show real benefits and harms later in childhood. To decrease the risk of generalisation and data-driven biased conclusions, we present a detailed description of the methodology for the SafeBoosC-III follow-up study. As funding is limited, a pragmatic approach is necessary.

Trial registration

ClinicalTrials.gov NCT05134116. Registered on 24 November 2021.
Genomic architecture of autism spectrum disorder in Qatar: The BARAKA-Qatar Study
Authors: Abdi Mona , Aliyev Elbay , Trost Brett , Kohailan Muhammad , Aamer Waleed , Syed Najeeb , Shaath Rulan , Gandhi Geethanjali Devadoss , Engchuan Worrawat , Howe Jennifer , Thiruvahindrapuram Bhooma , Geng Melissa , Whitney Joe , Syed Amira , Lakshmi Jyothi , Hussein Sura , Albashir Najwa , Hussein Amal , Poggiolini Ilaria , Elhag Saba F. , Palaniswamy Sasirekha , Kambouris Marios , de Fatima Janjua Maria , Tahir Mohamed O. El , Nazeer Ahsan , Shahwar Durre , Azeem Muhammad Waqar , Mokrab Younes , Aati Nazim Abdel , Akil Ammira , Scherer Stephen W. , Kamal Madeeha , Fakhro Khalid A.
Published: October 2023

Background

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social and communication skills, restricted interests, and repetitive behaviors. The prevalence of ASD among children in Qatar was recently estimated to be 1.1%, though the genetic architecture underlying ASD both in Qatar and the greater Middle East has been largely unexplored. Here, we describe the first genomic data release from the BARAKA-Qatar Study—a nationwide program building a broadly consented biorepository of individuals with ASD and their families available for sample and data sharing and multi-omics research.

Methods

In this first release, we present a comprehensive analysis of whole-genome sequencing (WGS) data of the first 100 families (372 individuals), investigating the genetic architecture, including single-nucleotide variants (SNVs), copy number variants (CNVs), tandem repeat expansions (TREs), as well as mitochondrial DNA variants (mtDNA) segregating with ASD in local families.

Results

Overall, we identify potentially pathogenic variants in known genes or regions in 27 out of 100 families (27%), of which 11 variants (40.7%) were classified as pathogenic or likely-pathogenic based on American College of Medical Genetics (ACMG) guidelines. Dominant variants, including de novo and inherited, contributed to 15 (55.6%) of these families, consisting of SNVs/indels (66.7%), CNVs (13.3%), TREs (13.3%), and mtDNA variants (6.7%). Moreover, homozygous variants were found in 7 families (25.9%), with a sixfold increase in homozygous burden in consanguineous versus non-consanguineous families (13.6% and 1.8%, respectively). Furthermore, 28 novel ASD candidate genes were identified in 20 families, 23 of which had recurrent hits in MSSNG and SSC cohorts.

Conclusions

This study illustrates the value of ASD studies in under-represented populations and the importance of WGS as a comprehensive tool for establishing a molecular diagnosis for families with ASD. Moreover, it uncovers a significant role for recessive variation in ASD architecture in consanguineous settings and provides a unique resource of Middle Eastern genomes for future research to the global ASD community.
Effects of iron homeostasis on epigenetic age acceleration: a two-sample Mendelian randomization study
Authors: Wang Zhihao , Liu Yi , Zhang Shuxin , Yuan Yunbo , Chen Siliang , Li Wenhao , Zuo Mingrong , Xiang Yufan , Li Tengfei , Yang Wanchun , Yang Yuan , Liu Yanhui
Published: October 2023

Background

Epigenetic clocks constructed from DNA methylation patterns have emerged as excellent predictors of aging and aging-related health outcomes. Iron, a crucial element, is meticulously regulated within organisms, a phenomenon referred as iron homeostasis. Previous researches have demonstrated the sophisticated connection between aging and iron homeostasis. However, their causal relationship remains relatively unexplored.

Results

Through two-sample Mendelian randomization (MR) utilizing the random effect inverse variance weighted (IVW) method, each standard deviation (SD) increase in serum iron was associated with increased GrimAge acceleration (GrimAA, BetaIVW = 0.27, P = 8.54E−03 in 2014 datasets; BetaIVW = 0.31, P = 1.25E−02 in 2021 datasets), HannumAge acceleration (HannumAA, BetaIVW = 0.32, P = 4.50E−03 in 2014 datasets; BetaIVW = 0.32, P = 8.03E−03 in 2021 datasets) and Intrinsic epigenetic age acceleration (IEAA, BetaIVW = 0.34, P = 5.33E−04 in 2014 datasets; BetaIVW = 0.49, P = 9.94E−04 in 2021 datasets). Similar results were also observed in transferrin saturation. While transferrin manifested a negative association with epigenetic age accelerations (EAAs) sensitivity analyses. Besides, lack of solid evidence to support a causal relationship from EAAs to iron-related biomarkers.

Conclusions

The results of present investigation unveiled the causality of iron overload on acceleration of epigenetic clocks. Researches are warranted to illuminate the underlying mechanisms and formulate strategies for potential interventions.
Primary hyperoxaluria: a case series
Authors: Rather Jawad Iqbal , Rasheed Rabiya , Wani Muzafar Maqsood , Bhat Mohammad Ashraf , Wani Imtiyaz Ahmad
Published: October 2023

Background

Primary hyperoxaluria (PH) is a rare genetic disorder characterized by the excessive production and accumulation of oxalate. We present five cases of PH, each exhibiting varying manifestations of the disorder including a case presenting as postpartum kidney failure. Notably, three of these cases involve a previously unreported mutation.

Case presentations

We evaluated five Indian patients who presented with varying manifestations of PH. The first case, a 30 year old woman, presented as post-partum kidney failure and was found to be having oxalate nephropathy precipitated by dietary oxalate overload in the setting of previously undiagnosed PH. Genetic analysis revealed a previously unreported mutation in the alanine-glyoxylate aminotransferase gene. The patient underwent simultaneous kidney liver transplant. The second and third cases, 26 and 28 year old women respectively, were asymptomatic siblings of the first patient, who were diagnosed through screening. The fourth case is a 12 year boy with PH type 1 presenting as nephrolithiasis and rapidly worsening kidney function requiring combined kidney liver kidney transplant. Case 5 is a 6 year old male child with type 2 PH presenting with nephrolithiasis, nephrocalcinosis and normal kidney function. All the patients were born to consanguineous parents.

Conclusions

Due to limited clinical suspicion and inadequate diagnostic resources in certain countries with limited resources, it is possible for PH to go undiagnosed. The manifestations of the disease can range from no noticeable symptoms to severe disease. Interestingly, in some individuals with primary hyperoxaluria, the disease may not exhibit any symptoms until it is triggered by a high intake of dietary oxalate.