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Nature Communications Jul 2024It is unclear whether polycystic ovary syndrome (PCOS) is an independent risk factor for adverse birth outcomes in the offspring of affected women. Here, we investigate... (Meta-Analysis)
Meta-Analysis
It is unclear whether polycystic ovary syndrome (PCOS) is an independent risk factor for adverse birth outcomes in the offspring of affected women. Here, we investigate the association of PCOS with birth outcomes in the offspring of women with PCOS overall and by potential confounders. This systematic review and meta-analysis included 73 studies and 92,881 offspring of women with and without PCOS from inception until 13 July 2022. We report that mothers with PCOS are younger and have higher body mass index (BMI) around conception and have greater gestational weight gain. The odds of preterm birth, fetal growth restriction and low birth weight are higher and mean birthweight is lower in PCOS of which a lower mean birthweight and a higher small for gestational age are probably independent of BMI. This work informed the recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome, emphasizing that PCOS status should be captured at pregnancy to identify risk and improve birth outcomes in the offspring.
Topics: Polycystic Ovary Syndrome; Humans; Female; Pregnancy; Premature Birth; Pregnancy Outcome; Infant, Newborn; Birth Weight; Infant, Low Birth Weight; Body Mass Index; Fetal Growth Retardation; Risk Factors; Pregnancy Complications; Adult; Infant, Small for Gestational Age; Gestational Weight Gain
PubMed: 38965241
DOI: 10.1038/s41467-024-49752-6 -
Scientific Reports Jul 2024METTL3 and METTL14 are traditionally posited to assemble the m6A methyltransferase complex in a stoichiometric 1:1 ratio, modulating mRNA fate via m6A modifications....
METTL3 and METTL14 are traditionally posited to assemble the m6A methyltransferase complex in a stoichiometric 1:1 ratio, modulating mRNA fate via m6A modifications. Nevertheless, recent investigations reveal inconsistent expression levels and prognostic significance of METTL3 and METTL14 across various tumor types, challenging their consistent functional engagement in neoplastic contexts. A pan-cancer analysis leveraging The Cancer Genome Atlas (TCGA) data has identified pronounced disparities in the expression patterns, functional roles, and correlations with tumor burden between METTL3 and METTL14, particularly in esophageal squamous cell carcinoma (ESCC). Knockdown experiments of METTL3 in EC109 cells markedly suppress cell proliferation both in vitro and in vivo, whereas METTL14 knockdown shows a comparatively muted effect on proliferation and does not significantly alter METTL3 protein levels. mRNA sequencing indicates that METTL3 singularly governs the expression of 1615 genes, with only 776 genes co-regulated with METTL14. Additionally, immunofluorescence co-localization studies suggest discrepancies in cellular localization between METTL3 and METTL14. High-performance liquid chromatography-mass spectrometry (HPLC-MS) analyses demonstrate that METTL3 uniquely associates with the Nop56p-linked pre-rRNA complex and mRNA splicing machinery, independent of METTL14. Preliminary bioinformatics and multi-omics investigations reveal that METTL3's autonomous role in modulating tumor cell proliferation and its involvement in mRNA splicing are potentially pivotal molecular mechanisms. Our study lays both experimental and theoretical groundwork for a deeper understanding of the m6A methyltransferase complex and the development of targeted tumor therapies focusing on METTL3.
Topics: Methyltransferases; Humans; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Disease Progression; Animals; Adenosine; Mice; RNA, Messenger
PubMed: 38965238
DOI: 10.1038/s41598-024-64517-3 -
Nature Communications Jul 2024Advancements in CRISPR technology, particularly the development of base editors, revolutionize genetic variant research. When combined with model organisms like...
Advancements in CRISPR technology, particularly the development of base editors, revolutionize genetic variant research. When combined with model organisms like zebrafish, base editors significantly accelerate and refine in vivo analysis of genetic variations. However, base editors are restricted by protospacer adjacent motif (PAM) sequences and specific editing windows, hindering their applicability to a broad spectrum of genetic variants. Additionally, base editors can introduce unintended mutations and often exhibit reduced efficiency in living organisms compared to cultured cell lines. Here, we engineer a suite of adenine base editors (ABEs) called ABE-Ultramax (Umax), demonstrating high editing efficiency and low rates of insertions and deletions (indels) in zebrafish. The ABE-Umax suite of editors includes ABEs with shifted, narrowed, or broadened editing windows, reduced bystander mutation frequency, and highly flexible PAM sequence requirements. These advancements have the potential to address previous challenges in disease modeling and advance gene therapy applications.
Topics: Zebrafish; Animals; Gene Editing; Adenine; CRISPR-Cas Systems; INDEL Mutation; RNA, Guide, CRISPR-Cas Systems; Animals, Genetically Modified; Alleles
PubMed: 38965236
DOI: 10.1038/s41467-024-49943-1 -
BDJ Open Jul 2024To evaluate educational impact of game-based learning (GBL) in orthodontic education.
OBJECTIVE
To evaluate educational impact of game-based learning (GBL) in orthodontic education.
METHODS
A systematic search was undertaken across four databases (Scopus, PubMed, ProQuest Dissertations & Theses Global, and Google Scholar) to identify relevant articles published from January 2000 to December 2023. Additionally, the reference lists of identified literature were examined to further search for relevant literature. The last search was performed on 28 January 2024.
RESULTS
Following the article selection process, seven articles were included in this systematic review, comprising four randomized control trials and three questionnaire surveys. Six articles were assessed to have a moderate risk of biases, whereas one research exhibited a low risk of bias. GBL interventions assessed in five articles were designed in digital format, while one study implemented evaluated traditional learning, and another employed a card game format. Two RCTs indicated a greater effectiveness of GBL in enhancing learner performance compared to traditional learning methods, while one article found no significant difference. Across all articles, positive perceptions of GBL were consistently highlighted at both undergraduate and postgraduate levels.
CONCLUSION
This systematic review supports the potential of GBL in orthodontic education. The implementation of GBL is recommended to integrate entertaining and educational elements, fostering learner performance within engaging learning environments. However, it is imperative to acknowledge that the overall quality of evidence is limited, primarily due to the moderate risk of biases identified in six of the included articles. Consequently, further high-quality experimental studies are required to validate the effectiveness of GBL in orthodontic education.
PubMed: 38965234
DOI: 10.1038/s41405-024-00218-3 -
Intracellular cartilage oligomeric matrix protein augments breast cancer resistance to chemotherapy.Cell Death & Disease Jul 2024Chemotherapy persists as the primary intervention for breast cancer, with chemoresistance posing the principal obstacle to successful treatment. Herein, we show that...
Chemotherapy persists as the primary intervention for breast cancer, with chemoresistance posing the principal obstacle to successful treatment. Herein, we show that cartilage oligomeric matrix protein (COMP) expression leads to increased cancer cell survival and attenuated apoptosis under treatment with several chemotherapeutic drugs, anti-HER2 targeted treatment, and endocrine therapy in several breast cancer cell lines tested. The COMP-induced chemoresistance was independent of the breast cancer subtype. Extracellularly delivered recombinant COMP failed to rescue cells from apoptosis while endoplasmic reticulum (ER)-restricted COMP-KDEL conferred resistance to apoptosis, consistent with the localization of COMP in the ER, where it interacted with calpain. Calpain activation was reduced in COMP-expressing cells and maintained at a lower level of activation during treatment with epirubicin. Moreover, the downstream caspases of calpain, caspases -9, -7, and -3, exhibited significantly reduced activation in COMP-expressing cells under chemotherapy treatment. Chemotherapy, when combined with calpain activators, rendered the cells expressing COMP more chemosensitive. Also, the anti-apoptotic proteins phospho-Bcl2 and survivin were increased in COMP-expressing cells upon chemotherapy. Cells expressing a mutant COMP lacking thrombospondin repeats exhibited reduced chemoresistance compared to cells expressing full-length COMP. Evaluation of calcium levels in the ER, cytosol, and mitochondria revealed that COMP expression modulates intracellular calcium homeostasis. Furthermore, patients undergoing chemotherapy or endocrine therapy demonstrated significantly reduced overall survival time when tumors expressed high levels of COMP. This study identifies a novel role of COMP in chemoresistance and calpain inactivation in breast cancer, a discovery with potential implications for anti-cancer therapy.
Topics: Humans; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Cartilage Oligomeric Matrix Protein; Cell Line, Tumor; Apoptosis; Calpain; Antineoplastic Agents; Endoplasmic Reticulum
PubMed: 38965233
DOI: 10.1038/s41419-024-06872-7 -
Nature Communications Jul 2024Epilepsy affects 1% of the general population and 30% of patients are resistant to antiepileptic drugs. Although optogenetics is an efficient antiepileptic strategy, the...
Epilepsy affects 1% of the general population and 30% of patients are resistant to antiepileptic drugs. Although optogenetics is an efficient antiepileptic strategy, the difficulty of illuminating deep brain areas poses translational challenges. Thus, the search of alternative light sources is strongly needed. Here, we develop pH-sensitive inhibitory luminopsin (pHIL), a closed-loop chemo-optogenetic nanomachine composed of a luciferase-based light generator, a fluorescent sensor of intracellular pH (EGFP), and an optogenetic actuator (halorhodopsin) for silencing neuronal activity. Stimulated by coelenterazine, pHIL experiences bioluminescence resonance energy transfer between luciferase and EGFP which, under conditions of acidic pH, activates halorhodopsin. In primary neurons, pHIL senses the intracellular pH drop associated with hyperactivity and optogenetically aborts paroxysmal activity elicited by the administration of convulsants. The expression of pHIL in hippocampal pyramidal neurons is effective in decreasing duration and increasing latency of pilocarpine-induced tonic-clonic seizures upon in vivo coelenterazine administration, without affecting higher brain functions. The same treatment is effective in markedly decreasing seizure manifestations in a murine model of genetic epilepsy. The results indicate that pHIL represents a potentially promising closed-loop chemo-optogenetic strategy to treat drug-refractory epilepsy.
Topics: Animals; Optogenetics; Hydrogen-Ion Concentration; Mice; Neurons; Epilepsy; Humans; Seizures; Halorhodopsins; Hippocampus; Male; Luciferases; Pyramidal Cells; Imidazoles; Pilocarpine; Disease Models, Animal; Mice, Inbred C57BL; HEK293 Cells; Pyrazines
PubMed: 38965228
DOI: 10.1038/s41467-024-49941-3 -
Translational Psychiatry Jul 2024Delirium is risky and indicates poor outcomes for patients. Therefore, it is crucial to create an effective delirium detection method. However, the epigenetic...
Delirium is risky and indicates poor outcomes for patients. Therefore, it is crucial to create an effective delirium detection method. However, the epigenetic pathophysiology of delirium remains largely unknown. We aimed to discover reliable and replicable epigenetic (DNA methylation: DNAm) markers that are associated with delirium including post-operative delirium (POD) in blood obtained from patients among four independent cohorts. Blood DNA from four independent cohorts (two inpatient cohorts and two surgery cohorts; 16 to 88 patients each) were analyzed using the Illumina EPIC array platform for genome-wide DNAm analysis. We examined DNAm differences in blood between patients with and without delirium including POD. When we compared top CpG sites previously identified from the initial inpatient cohort with three additional cohorts (one inpatient and two surgery cohorts), 11 of the top 13 CpG sites showed statistically significant differences in DNAm values between the delirium group and non-delirium group in the same directions as found in the initial cohort. This study demonstrated the potential value of epigenetic biomarkers as future diagnostic tools. Furthermore, our findings provide additional evidence of the potential role of epigenetics in the pathophysiology of delirium including POD.
Topics: Humans; Delirium; Female; Male; DNA Methylation; Epigenesis, Genetic; Aged; Middle Aged; Cohort Studies; CpG Islands; Postoperative Complications; Adult; Biomarkers; Aged, 80 and over
PubMed: 38965205
DOI: 10.1038/s41398-024-02986-w -
Journal of General Internal Medicine Jul 2024Women are the fastest growing veteran group in the US and the number of women veterans (WVs) with cancer is rising; however, little is known about this population....
BACKGROUND
Women are the fastest growing veteran group in the US and the number of women veterans (WVs) with cancer is rising; however, little is known about this population. Cancer care for WVs is complex and it is essential to understand their unique needs and care coordination challenges to provide evidence-based care. The purpose of this review is to map the quantity, distribution, and characteristics of literature describing cancer and its treatment among WVs.
METHODS
We searched MEDLINE (via PubMed), Embase (Elsevier), and Web of Science Core Collection (Clarivate) from inception through January, 2024. Publications were eligible that reported gender-specific data on any aspect of cancer care among WVs. Data was abstracted by a single investigator with over-reading.
RESULTS
Forty-six reports were included; 44 were observational and 19 had a women-only sample. There were no interventional reports and no qualitative reports had a patient sample. Breast cancer was the most commonly addressed (nā=ā19). There were six additional reports on sex-specific cancers. Many reports used large VA databases or previous trial data, creating the potential for patient overlap between reports. Among VA-specific areas of interest, only three reports evaluated the potential implications of racial differences and only two included a transgender population. No reports examined the effects of toxic exposures on cancer. Within the NCI Cancer Control Continuum, crosscutting areas were more commonly represented; over half (25) of the reports addressed epidemiology. There were few reports on focus areas and little overlap between focus and crosscutting areas.
DISCUSSION
Existing literature provides an inadequate understanding of the population of WVs with cancer. There is scant information regarding the population of WVs with cancer, their care preferences or experiences, or how to best identify and address unmet healthcare needs. It is imperative to expand research to provide evidence-based care for this population.
PubMed: 38965201
DOI: 10.1007/s11606-024-08903-7 -
Pharmacological Reports : PR Jul 2024Saikosaponin D, a saponin compound, is extracted from Bupleurum and is a principal active component of the plant. It boasts a variety of pharmacologic effects including... (Review)
Review
Saikosaponin D, a saponin compound, is extracted from Bupleurum and is a principal active component of the plant. It boasts a variety of pharmacologic effects including anti-inflammatory, antioxidant, immunomodulatory, metabolic, and anti-tumor properties, drawing significant attention in anti-tumor research in recent years. Research indicates that saikosaponin D inhibits the proliferation of numerous tumor cells, curbing the progression of cancers such as liver, pancreatic, lung, glioma, ovarian, thyroid, stomach, and breast cancer. Its anti-tumor mechanisms largely involve inhibiting tumor cell proliferation, promoting tumor cell apoptosis, thwarting tumor-cell invasion, and modulating tumor cell autophagy. Moreover, saikosaponin D enhances the sensitivity to anti-tumor drugs and augments body immunity. Given its multi-faceted anti-tumor roles, saikosaponin D offers promising potential in anti-tumor therapy. This paper reviews recent studies on its anti-tumor effects, aiming to furnish new theoretical insights for clinical cancer treatments.
PubMed: 38965200
DOI: 10.1007/s43440-024-00569-6 -
Clinical & Translational Oncology :... Jul 2024To develop and validate a serum protein nomogram for colorectal cancer (CRC) screening.
BACKGROUND
To develop and validate a serum protein nomogram for colorectal cancer (CRC) screening.
METHODS
The serum protein characteristics were extracted from an independent sample containing 30 colorectal cancer and 12 polyp tissues along with their paired samples, and different serum protein expression profiles were validated using RNA microarrays. The prediction model was developed in a training cohort that included 1345 patients clinicopathologically confirmed CRC and 518 normal participants, and data were gathered from November 2011 to January 2017. The lasso logistic regression model was employed for features selection and serum nomogram building. An internal validation cohort containing 576 CRC patients and 222 normal participants was assessed.
RESULTS
Serum signatures containing 27 secreted proteins were significantly differentially expressed in polyps and CRC compared to paired normal tissue, and REG family proteins were selected as potential predictors. The C-index of the nomogram1 (based on Lasso logistic regression model) which contains REG1A, REG3A, CEA and age was 0.913 (95% CI, 0.899 to 0.928) and was well calibrated. Addition of CA199 to the nomogram failed to show incremental prognostic value, as shown in nomogram2 (based on logistic regression model). Application of the nomogram1 in the independent validation cohort had similar discrimination (C-index, 0.912 [95% CI, 0.890 to 0.934]) and good calibration. The decision curve (DCA) and clinical impact curve (ICI) analysis demonstrated that nomogram1 was clinically useful.
CONCLUSIONS
This study presents a serum nomogram that included REG1A, REG3A, CEA and age, which can be convenient for screening of colorectal cancer.
PubMed: 38965192
DOI: 10.1007/s12094-024-03566-6