bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical practice guidelines for the antenatal management of dichorionic diamniotic twin pregnancies: a systematic review
Authors: O’Connor Caroline , O’Connor Emily , Leitao Sara , Barrett Shauna , O’Donoghue Keelin
Published: May 2023

Objective

This review aimed to identify guidelines with recommendations applicable to the antenatal management of dichorionic diamniotic twin pregnancies within high-income countries, appraise their methodological quality, and discuss the similarities and variability across guidelines.

Method

A systematic literature review of electronic databases was performed. Manual searches of guideline repositories and websites of professional organisations were performed to identify additional guidelines. The protocol for this systematic review was registered on PROSPERO (CRD42021248586, 25 June 2021). AGREE II and AGREE-REX tools were applied to assess the quality of eligible guidelines. A narrative and thematic synthesis described and compared the guidelines and their recommendations.

Results

Twenty-four guidelines were included, from which 483 recommendations were identified across 4 international organisations and 12 countries. Guidelines addressed eight themes and recommendations were classified accordingly: chorionicity and dating (103 recommendations), fetal growth (105 recommendations), termination of pregnancy (12 recommendations), fetal death (13 recommendations), fetal anomalies (65 recommendations), antenatal care (65 recommendations), preterm labour (56 recommendations) and birth (54 recommendations). Guidelines showed significant variability in recommendations, with conflicting recommendations regarding non-invasive preterm testing, definitions surrounding selective fetal growth restriction, screening for preterm labour and the timing of birth. Guidelines lacked a focus on standard antenatal management of DCDA twins, management of discordant fetal anomaly and single fetal demise.

Conclusions

Specific guidance for dichorionic diamniotic twins is overall indistinct and access to guidance regarding the antenatal management of these pregnancies is currently difficult. Management of discordant fetal anomaly or single fetal demise needs greater consideration.
How much do pregnant women know about the importance of oral health in pregnancy? Questionnaire-based survey
Authors: Radwan-Oczko Małgorzata , Hirnle Lidia , Szczepaniak Marta , Duś-Ilnicka Irena
Published: May 2023

Background

Although pregnancy is a physiological process it causes hormonal changes that can also affect the oral cavity. Pregnancy increases the risk of gum disease inflammation and tooth caries which could affect the health of the developing baby. Proper oral health is crucial both for mother and her babies and is related with mothers’ awareness of this connection. The aim of this study was the self-assessment of women’s both oral health and oral health literacy as well as mothers’ awareness of the connection of oral health and pregnancy.

Material and methods

In the study anonymous questionnaire was prepared and provided to be filled in by 200 mothers at the age from 19 to 44 y.o. who gave birth in the gynecological clinic. The questionnaire included demographic, and concerning the areas of oral health before and during pregnancy and after the childbirth questions.

Results

Only 20% of the investigated women underwent the oral examination before the pregnancy and the next 38.5% underwent it intentionally when the pregnancy had been confirmed. As much as 24% of women pointed out lack of awareness of the importance of proper oral hygiene during pregnancy.

41.5% of investigated women declared complaints during the pregnancy concerning teeth or gums and 30.5% underwent dental treatment; 68%, brushed their teeth properly—twice a day; 32% of women observed deterioration of oral health state during the pregnancy. The knowledge of the importance of oral health during pregnancy presented by the majority of mothers was relatively proper, which was strongly connected with higher education status and living in big cities. A significant correlation between higher birth weight and more frequent daily tooth brushing was observed. Both higher frequency of problems concerning the oral cavity and dental treatment during pregnancy were significantly related to the younger age of mothers.

Conclusions

The knowledge of women concerning of oral health on the management of pregnancy and development of fetus is still insufficient. Gynecologists should inquire pregnant women if they have done dental examination, and provide wider education about importance of oral health in pregnancy.
Hepatic passaging of NRAS-mutant melanoma influences adhesive properties and metastatic pattern
Authors: Dietsch Bianca , Weller Céline , Sticht Carsten , de la Torre Carolina , Kramer Martin , Goerdt Sergij , Géraud Cyrill , Wohlfeil Sebastian A.
Published: May 2023

Background

Liver metastasis is a poor prognostic factor for treatment of advanced cutaneous melanoma with either immunotherapy or targeted therapies. In this study we focused onNRASmutated melanoma, a cohort with high unmet clinical need.

Methods

WT31 melanoma was repeatedly passaged over the liver after intravenous injections five times generating the subline WT31_P5IV. The colonization of target organs, morphology, vascularization and the gene expression profiles of metastases were analyzed.

Results

After intravenous injection lung metastasis was significantly decreased and a trend towards increased liver metastasis was detected for WT31_P5IV as compared to parental WT31. Besides, the ratio of lung to liver metastases was significantly smaller. Histology of lung metastases revealed reduced proliferation of WT31_P5IV in relation to WT31 while both size and necrotic areas were unaltered. Liver metastases of both sublines showed no differences in vascularization, proliferation or necrosis. To identify tumor-intrinsic factors that altered the metastatic pattern of WT31_P5IV RNA sequencing was performed and revealed a differential regulation of pathways involved in cell adhesion. Ex vivo fluorescence imaging confirmed that initial tumor cell retention in the lungs was significantly reduced in WT31_P5IV in comparison to WT31.

Conclusion

This study demonstrates that tumor-intrinsic properties influencing the metastatic pattern ofNRASmutated melanoma are strongly affected by hepatic passaging and the hematogenous route tumor cells take. It has implications for the clinical setting as such effects might also occur during metastatic spread or disease progression in melanoma patients.
Biological evaluation of novel gemcitabine analog in patient-derived xenograft models of pancreatic cancer
Authors: Inkoom Andriana , Ndemazie Nkafu Bechem , Smith Taylor , Frimpong Esther , Bulusu Raviteja , Poku Rosemary , Zhu Xue , Han Bo , Trevino Jose , Agyare Edward
Published: May 2023

Gemcitabine (Gem) has been a standard first-line drug for pancreatic cancer (PCa) treatment; however, Gem's rapid metabolism and systemic instability (short half-life) limit its clinical outcome. The objective of this study was to modify Gem into a more stable form called 4-(N)-stearoyl-gemcitabine (4NSG) and evaluate its therapeutic efficacy in patient-derived xenograft (PDX) models from PCa of Black and White patients.

Methods 4NSG was synthesized and characterized using nuclear magnetic resonance (NMR), elemental analysis, and high-performance liquid chromatography (HPLC). 4NSG-loaded solid lipid nanoparticles (4NSG-SLN) were developed using the cold homogenization technique and characterized. Patient-derived pancreatic cancer cell lines labeled Black (PPCL-192, PPCL-135) and White (PPCL-46, PPCL-68) were used to assess the in vitro anticancer activity of 4NSG-SLN. Pharmacokinetics (PK) and tumor efficacy studies were conducted using PDX mouse models bearing tumors from Black and White PCa patients.

Results 4NSG was significantly stable in liver microsomal solution. The effective mean particle size (hydrodynamic diameter) of 4NSG-SLN was 82 ± 6.7 nm, and the half maximal inhibitory concentration (IC50) values of 4NSG-SLN treated PPCL-192 cells (9 ± 1.1 µM); PPCL-135 (11 ± 1.3 µM); PPCL-46 (12 ± 2.1) and PPCL-68 equaled to 22 ± 2.6 were found to be significantly lower compared to Gem treated PPCL-192 (57 ± 1.5 µM); PPCL-135 (56 ± 1.5 µM); PPCL-46 (56 ± 1.8 µM) and PPCL-68 (57 ± 2.4 µM) cells. The area under the curve (AUC), half-life, and pharmacokinetic clearance parameters for 4NSG-SLN were 3–fourfold higher than that of GemHCl. For in-vivo studies, 4NSG-SLN exhibited a two-fold decrease in tumor growth compared with GemHCl in PDX mice bearing Black and White PCa tumors.

Conclusion 4NSG-SLN significantly improved the Gem's pharmacokinetic profile, enhanced Gem's systemic stability increased its antitumor efficacy in PCa PDX mice bearing Black and White patient tumors.
Early resection of a rare congenital pulmonary airway malformation causing severe progressive respiratory distress in a preterm neonate: a case report and review of the literature
Authors: Ottomeyer Megan , Huddleston Charles , Berkovich Rachel M. , Brink David S. , Koenig Joyce M. , Sobush Kurtis T.
Published: May 2023

Background

Congenital pulmonary airway malformations (CPAMs) are a heterogenous collection of congenital lung malformations, often diagnosed prenatally. The Stocker Type III CPAM is a rare CPAM sub-type, and, when large, may be associated with hydrops. Furthermore, reports of CPAM management which may include surgical resection in extreme preterm infants are limited.

Case presentation

We report a case of a female neonate born at 28 weeks of gestation with severe respiratory distress and diffuse pulmonary opacification on the right concerning for a large congenital lung lesion. This lesion was not detected on routine antenatal imaging, and she did not have clinical findings of associated hydrops. Her respiratory status improved dramatically after surgical resection of a mass at 12 day of age. The mass was consistent pathologically with a Stocker Type III CPAM. Lung expansion showed subsequent improvement at 16 months of age.

Conclusions

Our case describes a preterm neonate with severe respiratory distress that was found postnatally to have a large, unilateral congenital lung lesion despite a normal prenatal ultrasound. Additionally, this lesion required excision early in life due to severity of respiratory compromise. This case highlights that rare congenital lung lesions, like this rare sub-type of CPAM, should remain a diagnostic consideration in neonates with severe respiratory distress. Early lung resection for CPAM in preterm infants is not well described and the favorable outcomes of this case help expand perspectives on potential management strategies.
Efficacy and safety of duloxetine in chronic musculoskeletal pain: a systematic review and meta-analysis
Authors: Ma Xuezhi , Zhou Shijie , Sun Wenyuan , Sun Jie , Li Guangguang , Wang Lining , Guo Yang
Published: May 2023

Background

Chronic musculoskeletal pain (CMP) is a complex condition that is mainly treated with analgesic drugs. However, antidepressant intervention is also an important factor in the treatment of CMP. Duloxetine is an effective treatment option for patients with CMP as its antidepressant effect. The purpose of this article is to evaluate the efficacy and safety of duloxetine in treating CMP.

Databases and data treatment

We searched PubMed, Web of Science, Embase, Cochrane Library from inception to May, 2022. Randomized controlled trials (RCTs) evaluating the efficacy and safety of duloxetine versus placebo in patients with CMP were included. We identified 13 articles and studied a population of 4201 participants in 4 countries.

Results

This meta-analysis showed that the duloxetine has statistically significant compared with the placebo control, benefits on 24-hour average pain, living quality, physical function, and global impressions and there was no difference in the incidence of serious adverse event. In general, duloxetine can improve mood and pain level at the same time.

Conclusions

This review shows a significant contribution of duloxetine to CMP symptom relief. This meta-analysis improved that duloxetine can significantly reduce the pain level of patients, improve depressive symptoms and global impression, and has no obvious serious adverse reactions. However, additional studies are required to confirm the relationship between psychological diseases and chronic pain and explore their internal links.
How are health technology assessment bodies responding to the assessment challenges posed by cell and gene therapy?
Authors: Drummond Michael , Ciani Oriana , Fornaro Giulia , Jommi Claudio , Dietrich Eva Susanne , Espin Jaime , Mossman Jean , de Pouvourville Gerard
Published: May 2023

Background

The aims of this research were to provide a better understanding of the specific evidence needs for assessment of clinical and cost-effectiveness of cell and gene therapies, and to explore the extent that the relevant categories of evidence are considered in health technology assessment (HTA) processes.

Methods

A targeted literature review was conducted to identify the specific categories of evidence relevant to the assessment of these therapies. Forty-six HTA reports for 9 products in 10 cell and gene therapy indications across 8 jurisdictions were analysed to determine the extent to which various items of evidence were considered.

Results

The items to which the HTA bodies reacted positively were: treatment was for a rare disease or serious condition, lack of alternative therapies, evidence indicating substantial health gains, and when alternative payment models could be agreed. The items to which they reacted negatively were: use of unvalidated surrogate endpoints, single arm trials without an adequately matched alternative therapy, inadequate reporting of adverse consequences and risks, short length of follow-up in clinical trials, extrapolating to long-term outcomes, and uncertainty around the economic estimates.

Conclusions

The consideration by HTA bodies of evidence relating to the particular features of cell and gene therapies is variable. Several suggestions are made for addressing the assessment challenges posed by these therapies. Jurisdictions conducting HTAs of these therapies can consider whether these suggestions could be incorporated within their existing approach through strengthening deliberative decision-making or performing additional analyses.
Improving the quality of care in nursing home organizations with urgent quality issues: design and effectiveness of a Dutch government-funded support programme
Authors: Vermunt Paulien , Reijmer Yael , van Biessum Clariska , de Groot Valerie , van den Berg Bellis , Nies Henk
Published: May 2023

Background

Various societal developments are currently challenging the ability of European nursing home organizations to meet quality standards. To support nursing home organizations throughout the Netherlands in quality improvement (QI), the Dutch government launched a nationwide programme in 2016 entitled ‘Dignity and pride’ (D&p). As part of this programme, participating nursing home organizations followed a tailored trajectory centred around intensive, on-site support from external expert coaches. For this study, we evaluated to what extent quality improvements were realized in the programme, paying particular attention to the role of the expert coaches.

Methods

Thirty-six nursing home organizations were included. At the start of D&p, the majority of these organizations (78%) had major quality issues as determined by the Health Care Inspectorate. Information on quality of care at the start versus end of the programme was obtained from improvement plans and final evaluation reports. Quality of person-centred care (PCC) and resident safety were quantified using a standardized assessment tool based on national guidelines, with improvements analysed using two-sided paired-sample T-tests. In addition, semi-structured interviews were conducted with 14 coaches and 29 healthcare professionals, focusing on the greatest benefits of programme participation and on the added value of the expert coaches.

Results

After completion of the programme, 60% of the organizations scored a 4 (= good) on PCC and resident safety, and none scored a 2 or less (average improvement on a 5-point scale for both themes: 1.9 points, p < 0.001). Interviewees confirmed that the quality of care had both improved and become more person-centred. The expert coaches were credited with substantially contributing to the QI process by offering an outsider’s perspective, bringing in experience and expertise, and helping the organization stay committed and focused.

Conclusions

Our study results suggest that the D&p programme was associated with improved quality of care in nursing home organizations with urgent quality issues. However, offering on-site tailored support through a nationally coordinated, government-funded programme is both time- and labour-intensive, and therefore not feasible in every healthcare setting. Nevertheless, the findings provide valuable insights for future QI support strategies.
A small protein coded within the mitochondrial canonical gene nd4 regulates mitochondrial bioenergetics
Authors: Kienzle Laura , Bettinazzi Stefano , Choquette Thierry , Brunet Marie , Khorami Hajar Hosseini , Jacques Jean-François , Moreau Mathilde , Roucou Xavier , Landry Christian R. , Angers Annie , Breton Sophie
Published: May 2023

Background

Mitochondria have a central role in cellular functions, aging, and in certain diseases. They possess their own genome, a vestige of their bacterial ancestor. Over the course of evolution, most of the genes of the ancestor have been lost or transferred to the nucleus. In humans, the mtDNA is a very small circular molecule with a functional repertoire limited to only 37 genes. Its extremely compact nature with genes arranged one after the other and separated by short non-coding regions suggests that there is little room for evolutionary novelties. This is radically different from bacterial genomes, which are also circular but much larger, and in which we can find genes inside other genes. These sequences, different from the reference coding sequences, are called alternatives open reading frames or altORFs, and they are involved in key biological functions. However, whether altORFs exist in mitochondrial protein-coding genes or elsewhere in the human mitogenome has not been fully addressed.

Results

We found a downstream alternative ATG initiation codon in the + 3 reading frame of the human mitochondrial nd4 gene. This newly characterized altORF encodes a 99-amino-acid-long polypeptide, MTALTND4, which is conserved in primates. Our custom antibody, but not the pre-immune serum, was able to immunoprecipitate MTALTND4 from HeLa cell lysates, confirming the existence of an endogenous MTALTND4 peptide. The protein is localized in mitochondria and cytoplasm and is also found in the plasma, and it impacts cell and mitochondrial physiology.

Conclusions

Many human mitochondrial translated ORFs might have so far gone unnoticed. By ignoring mtaltORFs, we have underestimated the coding potential of the mitogenome. Alternative mitochondrial peptides such as MTALTND4 may offer a new framework for the investigation of mitochondrial functions and diseases.
Spanish validation of the Pediatric Quality of Life Inventory (PedsQL™ 4.0) for parent report for toddlers (ages 2–4)
Authors: Martínez-Shaw Melissa Liher , del Río Francisco Javier , Sánchez-Sandoval Yolanda
Published: May 2023

Background/objective

Health-related quality of life is a concept that includes aspects about physical, emotional and social well-being. The aim of the study was to validate the PedsQL for parent report for toddlers in Spain and provide reference data in a Spanish population.

Method

The sample included 478 parents (89.5% mothers) of children aged 18–36 months (M = 26.75 months). Sociodemographic data were gathered, and the PedsQL and Kiddy-KINDL-R were completed by the participants.

Results

The fit of the original structure of the PedsQL was acceptable (CFI = 0.93; TLI = 0.92; RMSEA = 0.06), and the results showed good internal consistency (α = 0.85). The items about nursery school were excluded, since not all the toddlers attended this type of educational centre. Significant differences were found in physical health and activities and in the total mean in terms of parent education level, and in social activities regarding gender. For the normative interpretation of the PedsQL, the first, second and third quartiles corresponded to 77.78, 84.72 and 90.28, respectively.

Conclusions

This instrument is not only useful to individually evaluate the quality of life of a child with respect to his/her group, but also to measure the efficacy of a possible intervention.
Haploidentical transplants deliver equal outcomes to matched sibling transplants: a propensity score-matched analysis
Authors: Wu Hengwei , Zhao Yeqian , Gao Fei , Shi Jimin , Luo Yi , Yu Jian , Lai Xiaoyu , Liu Lizhen , Fu Huarui , Qian Pengxu , Huang He , Zhao Yanmin
Published: May 2023

The success of allogeneic hematopoietic stem cell transplant for hematological malignancies is heavily dependent on the availability of suitable donors. Haploidentical donor (HID) and matched sibling donor (MSD) are two important donor options providing faster and easier sources of stem cells, however, due to confounding factors present in most retrospective studies, the validity of comparing outcomes between these two donor types remains uncertain. We conducted a post-hoc analysis of a prospective clinical trial (trial registration: Chinese Clinical Trial Registry; #ChiCTR-OCH-12002490; registered 22 February 2012; https://www.chictr.org.cn/showproj.aspx?proj=7061) to compare outcomes of HID versus MSD peripheral blood stem cell-derived transplants in patients with hematologic malignancies between 2015 and 2022. All HID-receiving patients had antithymocyte globulin-based conditioning. Propensity score matching was employed to minimize potential confounding factors between the two cohorts. A total of 1060 patients were initially reviewed and then 663 patients were ultimately included in the analysis after propensity score matching. The overall survival, relapse-free survival, non-relapse mortality rate and cumulative incidence of relapse were similar between HID and MSD cohorts. Subgroup analysis revealed that patients with positive measurable residual disease in first complete remission may have better overall survival with an HID transplant. The present demonstrated that haploidentical transplants can provide outcomes comparable to conventional MSD transplants, and HID should be recommended as one of the optimal donor choices for patients with positive measurable residual disease in first complete remission.
Proteomics and cytokine analyses distinguish myalgic encephalomyelitis/chronic fatigue syndrome cases from controls
Authors: Giloteaux Ludovic , Li Jiayin , Hornig Mady , Lipkin W. Ian , Ruppert David , Hanson Maureen R.
Published: May 2023

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogenous disease characterized by unexplained persistent fatigue and other features including cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Cytokines are present in plasma and encapsulated in extracellular vesicles (EVs), but there have been only a few reports of EV characteristics and cargo in ME/CFS. Several small studies have previously described plasma proteins or protein pathways that are associated with ME/CFS.

Methods

We prepared extracellular vesicles (EVs) from frozen plasma samples from a cohort of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) cases and controls with prior published plasma cytokine and plasma proteomics data. The cytokine content of the plasma-derived extracellular vesicles was determined by a multiplex assay and differences between patients and controls were assessed. We then performed multi-omic statistical analyses that considered not only this new data, but extensive clinical data describing the health of the subjects.

Results

ME/CFS cases exhibited greater size and concentration of EVs in plasma. Assays of cytokine content in EVs revealed IL2 was significantly higher in cases. We observed numerous correlations among EV cytokines, among plasma cytokines, and among plasma proteins from mass spectrometry proteomics. Significant correlations between clinical data and protein levels suggest roles of particular proteins and pathways in the disease. For example, higher levels of the pro-inflammatory cytokines Granulocyte-Monocyte Colony-Stimulating Factor (CSF2) and Tumor Necrosis Factor (TNFα) were correlated with greater physical and fatigue symptoms in ME/CFS cases. Higher serine protease SERPINA5, which is involved in hemostasis, was correlated with higher SF-36 general health scores in ME/CFS. Machine learning classifiers were able to identify a list of 20 proteins that could discriminate between cases and controls, with XGBoost providing the best classification with 86.1% accuracy and a cross-validated AUROC value of 0.947. Random Forest distinguished cases from controls with 79.1% accuracy and an AUROC value of 0.891 using only 7 proteins.

Conclusions

These findings add to the substantial number of objective differences in biomolecules that have been identified in individuals with ME/CFS. The observed correlations of proteins important in immune responses and hemostasis with clinical data further implicates a disturbance of these functions in ME/CFS.
Dual trajectories of antiretroviral therapy adherence and polypharmacy in women with HIV in the United States
Authors: Elbur Abubaker Ibrahim , Ghebremichael Musie , Konkle-Parker Deborah , Jones Deborah L , Collins Shelby , Adimora Adaora A. , Schneider Michael F. , Cohen Mardge H. , Tamraz Bani , Plankey Michael , Wilson Tracey , Adedimeji Adebola , Haberer Jessica E. , Jacobson Denise L.
Published: May 2023

Background

Polypharmacy, using five or more medications, may increase the risk of nonadherence to prescribed treatment. We aimed to identify the interrelationship between trajectories of adherence to antiretroviral therapy (ART) and polypharmacy.

Methods

We included women with HIV (aged ≥ 18) enrolled in the Women’s Interagency HIV Study in the United States from 2014 to 2019. We used group-based trajectory modeling (GBTM) to identify trajectories of adherence to ART and polypharmacy and the dual GBTM to identify the interrelationship between adherence and polypharmacy.

Results

Overall, 1,538 were eligible (median age of 49 years). GBTM analysis revealed five latent trajectories of adherence with 42% of women grouped in the consistently moderate trajectory. GBTM identified four polypharmacy trajectories with 45% categorized in the consistently low group.

Conclusions

The joint model did not reveal any interrelationship between ART adherence and polypharmacy trajectories. Future research should consider examining the interrelationship between both variables using objective measures of adherence.
Molecular mechanisms involved in regulating protein activity and biological function of MST3
Authors: Qiu Jing , Xiong Junzhi , Jiang Lu , Wang Xinmin , Zhang Kebin , Yu Hua
Published: May 2023

Mammalian sterile 20-like (Ste20-like) protein kinase 3 (MST3) or serine/threonine-protein kinase 24 (STK24) is a serine/threonine protein kinase that belongs to the mammalian STE20-like protein kinase family. MST3 is a pleiotropic protein that plays a critical role in regulating a variety of events, including apoptosis, immune response, metabolism, hypertension, tumor progression, and development of the central nervous system. The MST3-mediated regulation is intricately related to protein activity, post-translational modification, and subcellular location. Here, we review the recent progress on the regulatory mechanisms against MST3 and its-mediated control of disease progression.
Identification of upregulated exosomal miRNAs between A2780 and A2780/DDP human ovarian cancer cells by high-throughput sequencing
Authors: Wang Huihui , Liu Li , Liu Qinying , Zheng Jianfeng , Zheng Qiuhong , Chen Yuwei , Xia Hongmei , Wu Qiaoling , Sun Yang
Published: May 2023

Exosomal miRNAs are known to play important roles in ovarian cancer and chemotherapeutic resistance. However, a systematic evaluation of characteristics of exosomal miRNAs involved in cisplatin resistance in ovarian cancer remains totally unclear. Exosomes (Exo-A2780, Exo-A2780/DDP) were extracted from cisplatin-sensitive cells (A2780) and cisplatin-resistant cells (A2780/DDP). Differential exosomal miRNA expression profiles were found by high-throughput sequencing (HTS). Target genes of the exo-miRNAs were predicted by using two online databases to increase the prediction accuracy. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were utilized to find biological relationships with chemoresistance. RT‒qPCR of three exosomal miRNAs was performed, and a protein‒protein interaction (PPI) network was established to identify the hub genes. The GDSC database was used to prove the association between hsa-miR-675-3p expression and the IC50 value. An integrated miRNA–mRNA network was constructed to predict miRNA–mRNA associations. The connection between hsa-miR-675-3p and ovarian cancer was discovered by immune microenvironment analyses. The upregulated exosomal miRNAs could regulate gene targets through signalling pathways such as the Ras, PI3K/Akt, Wnt, and ErbB pathways. GO and KEGG analyses indicated that the target genes were involved in protein binding, transcription regulator activity and DNA binding. The RT‒qPCR results were consistent with the HTS data, and the results of PPI network analysis suggested that FMR1 and CD86 were the hub genes. GDSC database analysis and construction of the integrated miRNA–mRNA network suggested that hsa-miR-675-3p was associated with drug resistance. Immune microenvironment analyses showed that hsa-miR-675-3p was crucial in ovarian cancer. The study suggested that exosomal hsa-miR-675-3p is a potential target for treating ovarian cancer and overcoming cisplatin resistance.
Lymphocyte-activation gene 3 protein expression in tumor-infiltrating lymphocytes is associated with a poor prognosis of ovarian clear cell carcinoma
Authors: Zaitsu Sumika , Yano Mitsutake , Adachi Sawako , Miwa Maiko , Katoh Tomomi , Kawano Yasushi , Yasuda Masanori
Published: May 2023

Background

Histological analysis has revealed the need for new treatment techniques for epithelial ovarian cancer. Immune checkpoint inhibitors may be a new therapeutic strategy for ovarian clear cell carcinoma (OCCC). Lymphocyte-activation gene 3 (LAG-3), an immune checkpoint, is a poor prognostic factor and a new therapeutic target for several malignancies. In this study, we demonstrated the correlation between LAG-3 expression and the clinicopathological features of OCCC. We evaluated LAG-3 expression in tumor-infiltrating lymphocytes (TILs) via immunohistochemical analysis using tissue microarrays containing surgically resected specimens from 171 patients with OCCC.

Results

The number of LAG-3-positive cases was 48 (28.1%), whereas the number of LAG-3-negative cases was 123 (71.9%). LAG-3 expression significantly increased in patients with advanced stages (P = 0.036) and recurrence (P = 0.012); however, its expression did not correlate with age (P = 0.613), residual tumor (P = 0.156), or death (P = 0.086). Using the Kaplan − Meier method, LAG-3 expression was found to be correlated with poor overall survival (P = 0.020) and progression-free survival (P = 0.019). Multivariate analysis revealed LAG-3 expression (hazard ratio [HR] = 1.86; 95% confidence interval [CI], 1.00 − 3.44, P = 0.049) and residual tumor (HR = 9.71; 95% CI, 5.13 − 18.52, P < 0.001) as independent prognostic factors.

Conclusion

Our study demonstrated that LAG-3 expression in patients with OCCC may be a useful biomarker for the prognosis of OCCC and could serve as a new therapeutic target.
Multidrug resistant 1 (MDR1) C3435T and G2677T gene polymorphism: impact on the risk of acute rejection in pediatric kidney transplant recipients
Authors: Korkor Mai S , el-desoky Tarek , Mosaad Youssef M , Salah Doaa M. , Hammad Ayman
Published: May 2023

Background

Tacrolimus is the backbone drug in kidney transplantation. Single nucleotide polymorphism of Multidrug resistant 1 gene can affect tacrolimus metabolism consequently it can affect tacrolimus trough level and incidence of acute rejection. The aim of this study is to investigate the impact of Multidrug resistant 1 gene, C3435T and G2677T Single nucleotide polymorphisms on tacrolimus pharmacokinetics and on the risk of acute rejection in pediatric kidney transplant recipients.

Methods

Typing of Multidrug resistant 1 gene, C3435T and G2677T gene polymorphism was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for 83 pediatric kidney transplant recipients and 80 matched healthy controls.

Results

In Multidrug resistant 1 gene (C3435T), CC, CT genotypes and C allele were significantly associated with risk of acute rejection when compared to none acute rejection group (P = 0.008, 0.001 and 0.01 respectively). The required tacrolimus doses to achieve trough level were significantly higher among CC than CT than TT genotypes through the 1st 6 months after kidney transplantation. While, in Multidrug resistant 1 gene (G2677T), GT, TT genotypes and T allele were associated with acute rejection when compared to none acute rejection (P = 0.023, 0.033 and 0.028 respectively). The required tacrolimus doses to achieve trough level were significantly higher among TT than GT than GG genotypes through the 1st 6 months after kidney transplantation.

Conclusion

The C allele, CC and CT genotypes of Multidrug resistant 1 gene (C3435T) and the T allele, GT and TT genotypes of Multidrug resistant 1 gene (G2677T) gene polymorphism may be risk factors for acute rejection and this can be attributed to their effect on tacrolimus pharmacokinetics. Tacrolimus therapy may be tailored according to the recipient genotype for better outcome.
The pattern of histone H3 epigenetic posttranslational modifications is regulated by the VRK1 chromatin kinase
Authors: Monte-Serrano Eva , Morejón-García Patricia , Campillo-Marcos Ignacio , Campos-Díaz Aurora , Navarro-Carrasco Elena , Lazo Pedro A.
Published: May 2023

Background

Dynamic chromatin remodeling is associated with changes in the epigenetic pattern of histone acetylations and methylations required for processes based on dynamic chromatin remodeling and implicated in different nuclear functions. These histone epigenetic modifications need to be coordinated, a role that may be mediated by chromatin kinases such as VRK1, which phosphorylates histones H3 and H2A.

Methods

The effect of VRK1 depletion and VRK1 inhibitor, VRK-IN-1, on the acetylation and methylation of histone H3 in K4, K9 and K27 was determined under different conditions, arrested or proliferating cells, in A549 lung adenocarcinoma and U2OS osteosarcoma cells.

Results

Chromatin organization is determined by the phosphorylation pattern of histones mediated by different types of enzymes. We have studied how the VRK1 chromatin kinase can alter the epigenetic posttranslational modifications of histones by using siRNA, a specific inhibitor of this kinase (VRK-IN-1), and of histone acetyl and methyl transferases, as well as histone deacetylase and demethylase. Loss of VRK1 implicated a switch in the state of H3K9 posttranslational modifications. VRK1 depletion/inhibition causes a loss of H3K9 acetylation and facilitates its methylation. This effect is similar to that of the KAT inhibitor C646, and to KDM inhibitors as iadademstat (ORY-1001) or JMJD2 inhibitor. Alternatively, HDAC inhibitors (selisistat, panobinostat, vorinostat) and KMT inhibitors (tazemetostat, chaetocin) have the opposite effect of VRK1 depletion or inhibition, and cause increase of H3K9ac and a decrease of H3K9me3. VRK1 stably interacts with members of these four enzyme families. However, VRK1 can only play a role on these epigenetic modifications by indirect mechanisms in which these epigenetic enzymes are likely targets to be regulated and coordinated by VRK1.

Conclusions

The chromatin kinase VRK1 regulates the epigenetic patterns of histone H3 acetylation and methylation in lysines 4, 9 and 27. VRK1 is a master regulator of chromatin organization associated with its specific functions, such as transcription or DNA repair.
Stress granules: functions and mechanisms in cancer
Authors: Zhou Huan , Luo Jing , Mou Kelin , Peng Lin , Li Xiaoyue , Lei Yulin , Wang Jianmei , Lin Sheng , Luo Yuhao , Xiang Li
Published: May 2023

Stress granules (SGs) are non-enveloped structures formed primarily via protein and RNA aggregation under various stress conditions, including hypoxia and viral infection, as well as oxidative, osmotic, and heat-shock stress. SGs assembly is a highly conserved cellular strategy to reduce stress-related damage and promote cell survival. At present, the composition and dynamics of SGs are well understood; however, data on the functions and related mechanisms of SGs are limited. In recent years, SGs have continued to attract attention as emerging players in cancer research. Intriguingly, SGs regulate the biological behavior of tumors by participating in various tumor-associated signaling pathways, including cell proliferation, apoptosis, invasion and metastasis, chemotherapy resistance, radiotherapy resistance, and immune escape. This review discusses the roles and mechanisms of SGs in tumors and suggests novel directions for cancer treatment.
Membrane tension-mediated stiff and soft tumor subtypes closely associated with prognosis for prostate cancer patients
Authors: Feng Dechao , Wang Jie , Shi Xu , Li Dengxiong , Wei Wuran , Han Ping
Published: May 2023

Background

Prostate cancer (PCa) is usually considered as cold tumor. Malignancy is associated with cell mechanic changes that contribute to extensive cell deformation required for metastatic dissemination. Thus, we established stiff and soft tumor subtypes for PCa patients from perspective of membrane tension.

Methods

Nonnegative matrix factorization algorithm was used to identify molecular subtypes. We completed analyses using software R 3.6.3 and its suitable packages.

Results

We constructed stiff and soft tumor subtypes using eight membrane tension-related genes through lasso regression and nonnegative matrix factorization analyses. We found that patients in stiff subtype were more prone to biochemical recurrence than those in soft subtype (HR 16.18; p < 0.001), which was externally validated in other three cohorts. The top ten mutation genes between stiff and soft subtypes were DNAH, NYNRIN, PTCHD4, WNK1, ARFGEF1, HRAS, ARHGEF2, MYOM1, ITGB6 and CPS1. E2F targets, base excision repair and notch signaling pathway were highly enriched in stiff subtype. Stiff subtype had significantly higher TMB and T cells follicular helper levels than soft subtype, as well as CTLA4, CD276, CD47 and TNFRSF25.

Conclusions

From the perspective of cell membrane tension, we found that stiff and soft tumor subtypes were closely associated with BCR-free survival for PCa patients, which might be important for the future research in the field of PCa.
Breast cancer prediction using gated attentive multimodal deep learning
Authors: Kayikci Safak , Khoshgoftaar Taghi M.
Published: May 2023

Women are prone to breast cancer, which is a major cause of death. One out of every eight women has a lifetime risk of developing this cancer. Early diagnosis of this disease is critical and enhances the success rate of cure. It is extremely important to determine which genes are associated with the disease. However, too many features make studies on gene data challenging. In this study, an attention-based multimodal deep learning model was created by combining data from clinical, copy number alteration and gene expression sources. Attention-based deep learning models can analyze mammography images and identify subtle patterns or abnormalities that may indicate the presence of cancer. These models can also integrate patient data, such as age and family history, to improve the accuracy of predictions. The objective of this study is to help breast cancer prediction tasks and improve efficiency by incorporating attention mechanisms. Our suggested methodology employs multimodal data and generates insightful characteristics to improve the prediction of the prognosis for breast cancer. It is a two-phase model; the first phase generates the stacked features using a sigmoid gated attention convolutional neural network, and the second phase uses flatten, dense and dropout processes for bi-modal attention. Based on our findings, the proposed model produced successful results and has the potential to significantly improve breast cancer detection and diagnosis, ultimately leading to better patient outcomes.
The incidence of hypotension during general anesthesia: a single-center study at a university hospital
Authors: Katori Nobuyuki , Yamakawa Kentaro , Kida Kotaro , Kimura Yoshihiro , Fujioka Shoko , Tsubokawa Tsunehisa
Published: May 2023

Background

Although intraoperative hypotension (IOH) has been emerging as a serious concern during general anesthesia, the incidence of IOH has not been demonstrated clearly in the Japanese population.

Methods

This single-center retrospective study investigated the incidence and the characteristics of IOH in non-cardiac surgery at a university hospital. IOH was defined as at least one fall of MAP during general anesthesia, which was categorized into the following groups: mild (65 to < 75 mmHg), moderate (55 to < 65 mmHg), severe (45 to < 55 mmHg), and very severe (< 45 mmHg). The incidence of IOH was calculated as a percentage of the number of events to the total anesthesia cases. Logistic regression analysis was performed to examine factors affecting IOH.

Results

Eleven thousand two hundred ten cases out of 13,226 adult patients were included in the analysis. We found moderate to very severe hypotension occurred in 86.3% of the patients for at least 1 to 5 min, and 48.5% experienced severe or very severe hypotension. The results of the logistic regression analysis indicated female gender, vascular surgery, American Society of Anesthesiologists physical status classification (ASA-PS) 4 or 5 in emergency surgery, and the combination with the epidural block (EDB) were significant factors of IOH.

Conclusions

IOH during general anesthesia was very frequent in the Japanese population. Female gender, vascular surgery, ASA-PA 4 or 5 in emergency surgery, and the combination with EDB were independent risk factors associated with IOH. However, the association with patient outcomes were not elucidated.
Low Circulating Valine Associate With High Risk of Hip Fractures
Authors: Grahnemo Louise , Eriksson Anna L , Nethander Maria , Johansson Robert , Lorentzon Mattias , Mellström Dan , Pettersson-Kymmer Ulrika , Ohlsson Claes
Published: May 2023

Context

Hip fractures constitute a major health concern. An adequate supply of amino acids is crucial to ensure optimal acquisition and remodeling of bone. Circulating amino acid levels have been proposed as markers of bone mineral density, but data on their ability to predict incident fractures are scarce.

Objectives

To investigate the associations between circulating amino acids and incident fractures.

Methods

We used UK Biobank (n = 111 257; 901 hip fracture cases) as a discovery cohort and the Umeå Fracture and Osteoporosis (UFO) hip fracture study (hip fracture cases n = 2225; controls n = 2225) for replication. Associations with bone microstructure parameters were tested in a subsample of Osteoporotic Fractures in Men Sweden (n = 449).

Results

Circulating valine was robustly associated with hip fractures in the UK Biobank (HR per SD increase 0.79, 95% CI 0.73-0.84), and this finding was replicated in the UFO study (combined meta-analysis including 3126 incident hip fracture cases, odds ratio per SD increase 0.84, 95% CI 0.80-0.88). Detailed bone microstructure analyses showed that high circulating valine was associated with high cortical bone area and trabecular thickness.

Conclusion

Low circulating valine is a robust predictor of incident hip fractures. We propose that circulating valine may add information for hip fracture prediction. Future studies are warranted to determine whether low valine is causally associated with hip fractures.
Sports Participation and Sports-Related Neurologic Injuries in Pediatric Patients With Arachnoid Cysts
Authors: Lee Johan H. , Holste Katherine G. , Selzer Bela J. , Garton Hugh J. L. , Muraszko Karin M. , Maher Cormac O.
Published: May 2023

BACKGROUND:

Currently, there is no consensus recommendation regarding the safety of sports participation for pediatric patients with arachnoid cysts (ACs).

OBJECTIVE:

To prospectively survey patients with ACs to define the risk of sports-associated neurologic injury in untreated and treated patients.

METHODS:

A prospectively administered survey was given to all patients diagnosed with an AC who presented to a single pediatric neurosurgery clinic between December 2010 and December 2021. Data were recorded on demographic information, imaging characteristics, treatment, sports participation, and presence of sports-related neurologic injury. The type and date of surgery for the AC were noted if surgery was performed.

RESULTS:

Of the 303 patients with completed surveys, 189 patients participated in sports, and 94 patients had prospective data available. There was no significant difference in cyst location or Galassi score between patients who did and did not participate in contact vs noncontact sports and those who did and did not experience a concussion. A cumulative total of 2700.5 seasons of sports were played (2499.7 in untreated and 200.8 in treated patients). There were 44 sports-related concussions among 34 patients: 43 in untreated patients and 1 in a treated patient. For all participants, the concussion rate was 16.3 per 1000 seasons of all sports and 14.8 per 1000 seasons of contact sports. The concussion rate after AC treatment was 4.9 per 1000 seasons of all sports. Three patients experienced sports-related AC rupture or hemorrhage, none of which required surgery or resulted in lasting neurologic symptoms or deficits.

CONCLUSION:

The rates of sports-related concussion and cyst rupture in patients with AC in both treated and untreated populations were low. We advocate for a generally permissive posture toward sports participation in this population.