One-carbon metabolism supports S-adenosylmethionine and m6A methylation to control the osteogenesis of bone marrow stem cells and bone formation.

The skeleton is a metabolically active organ undergoing continuous remodeling initiated by bone marrow stem cells (BMSCs). Recent research has demonstrated that BMSCs adapt the metabolic pathways to drive the osteogenic differentiation and bone formation, but the mechanism involved remains largely elusive. Here, using a comprehensive targeted metabolome and transcriptome profiling, we revealed that one-carbon metabolism was promoted following osteogenic induction of BMSCs. Methotrexate (MTX), an inhibitor of one-carbon metabolism that blocks S-adenosylmethionine (SAM) generation, led to decreased N6-methyladenosine (m6A) methylation level and inhibited osteogenic capacity. Increasing intracellular SAM generation through betaine addition rescued the suppressed m6A content and osteogenesis in MTX-treated cells. Using S-adenosylhomocysteine (SAH) to inhibit the m6A level, the osteogenic activity of BMSCs was consequently impeded. We also demonstrated that the pro-osteogenic effect of m6A methylation mediated by one-carbon metabolism could be attributed to HIF-1α and glycolysis pathway. This was supported by the findings that dimethyloxalyl glycine rescued the osteogenic potential in MTX-treated and SAH-treated cells by upregulating HIF-1α and key glycolytic enzymes expression. Importantly, betaine supplementation attenuated MTX-induced m6A methylation decrease and bone loss via promoting the abundance of SAM in rat. Collectively, these results revealed that one-carbon metabolite SAM was a potential promoter in BMSC osteogenesis via the augmentation of m6A methylation, and the cross talk between metabolic reprogramming, epigenetic modification, and transcriptional regulation of BMSCs might provide strategies for bone regeneration.

The bone is a self-renewing tissue that continues to reshape throughout life. Bone marrow mesenchymal stem cells (BMSCs) are essential for bone homeostasis as they are capable of osteogenic differentiation. Recent evidence suggests that BMSCs drive the osteogenic differentiation through metabolic reprogramming, but the mechanism remains unclear. In this paper, we explored the metabolic alteration following osteogenic induction of BMSCs and found that one-carbon metabolism was obviously promoted in this process. The underlining mechanisms of the osteogenic potential driven by one-carbon metabolism seem to be its contribution on N6-methyladenosine (m6A) methylation and consequent glycolysis level by providing methyl donor. We demonstrated that one-carbon metabolism-mediated m6A methylation was a potential promoter in BMSC osteogenesis, and metabolic-epigenetic coupling might provide novel therapeutic targets for bone regeneration.

The m6A eraser FTO suppresses ferroptosis via mediating ACSL4 in LPS-induced macrophage inflammation.

Acute lung injury (ALI) is a serious disorder characterized by the release of pro-inflammatory cytokines and cascade activation of macrophages. Ferroptosis, a form of iron-dependent cell death triggered by intracellular phospholipid peroxidation, has been implicated as an internal mechanism underlying ALI. In this study, we investigated the effects of m6A demethylase fat mass and obesity-associated protein (FTO) on the inhibition of macrophage ferroptosis in ALI. Using a mouse model of lipopolysaccharide (LPS)-induced ALI, we observed the induction of ferroptosis and its co-localization with the macrophage marker F4/80, suggesting that ferroptosis might be induced in macrophages. Ferroptosis was promoted during LPS-induced inflammation in macrophages in vitro, and the inflammation was counteracted by the ferroptosis inhibitor ferrostatin-1 (fer-1). Given that FTO showed lower expression levels in the lung tissue of mice with ALI and inflammatory macrophages, we further dissected the regulatory capacity of FTO in ferroptosis. The results demonstrated that FTO alleviated macrophage inflammation by inhibiting ferroptosis. Mechanistically, FTO decreased the stability of ACSL4 mRNA via YTHDF1, subsequently inhibiting ferroptosis and inflammation by interrupting polyunsaturated fatty acid consumption. Moreover, FTO downregulated the synthesis and secretion of prostaglandin E2, thereby reducing ferroptosis and inflammation. In vivo, the FTO inhibitor FB23-2 aggravated lung injury, the inflammatory response, and ferroptosis in mice with ALI; however, fer-1 therapy mitigated these effects. Overall, our findings revealed that FTO may function as an inhibitor of the inflammatory response driven by ferroptosis, emphasizing its potential as a target for ALI treatment.

Acetyl-CoA-dependent ac4C acetylation promotes the osteogenic differentiation of LPS-stimulated BMSCs.

The impaired osteogenic capability of bone marrow mesenchymal stem cells (BMSCs) caused by persistent inflammation is the main pathogenesis of inflammatory bone diseases. Recent studies show that metabolism is disturbed in osteogenically differentiated BMSCs in response to Lipopolysaccharide (LPS) treatment, while the mechanism involved remains incompletely revealed. Herein, we demonstrated that BMSCs adapted their metabolism to regulate acetyl-coenzyme A (acetyl-CoA) availability and RNA acetylation level, ultimately affecting osteogenic differentiation. The mitochondrial dysfunction and impaired osteogenic potential upon inflammatory conditions accompanied by the reduced acetyl-CoA content, which in turn suppressed N4-acetylation (ac4C) level. Supplying acetyl-CoA by sodium citrate (SC) addition rescued ac4C level and promoted the osteogenic capacity of LPS-treated cells through the ATP citrate lyase (ACLY) pathway. N-acetyltransferase 10 (NAT10) inhibitor remodelin reduced ac4C level and consequently impeded osteogenic capacity. Meanwhile, the osteo-promotive effect of acetyl-CoA-dependent ac4C might be attributed to fatty acid oxidation (FAO), as evidenced by activating FAO by L-carnitine supplementation counteracted remodelin-induced inhibition of osteogenesis. Further in vivo experiments confirmed the promotive role of acetyl-CoA in the endogenous bone regeneration in rat inflammatory mandibular defects. Our study uncovered a metabolic-epigenetic axis comprising acetyl-CoA and ac4C modification in the process of inflammatory osteogenesis of BMSCs and suggested a new target for bone tissue repair in the context of inflammatory bone diseases.

Clinical metabolomics characteristics of diabetic kidney disease: A meta-analysis of 1875 cases with diabetic kidney disease and 4503 controls.

AIMS: Diabetic Kidney Disease (DKD), one of the major complications of diabetes, is also a major cause of end-stage renal disease. Metabolomics can provide a unique metabolic profile of the disease and thus predict or diagnose the development of the disease. Therefore, this study summarises a more comprehensive set of clinical biomarkers related to DKD to identify functional metabolites significantly associated with the development of DKD and reveal their driving mechanisms for DKD. MATERIALS AND METHODS: We searched PubMed, Embase, the Cochrane Library and Web of Science databases through October 2022. A meta-analysis was conducted on untargeted or targeted metabolomics research data based on the strategy of standardized mean differences and the process of ratio of means as the effect size, respectively. We compared the changes in metabolite levels between the DKD patients and the controls and explored the source of heterogeneity through subgroup analyses, sensitivity analysis and meta-regression analysis. RESULTS: The 34 clinical-based metabolomics studies clarified the differential metabolites between DKD and controls, containing 4503 control subjects and 1875 patients with DKD. The results showed that a total of 60 common differential metabolites were found in both meta-analyses, of which 5 metabolites (p < 0.05) were identified as essential metabolites. Compared with the control group, metabolites glycine, aconitic acid, glycolic acid and uracil decreased significantly in DKD patients; cysteine was significantly higher. This indicates that amino acid metabolism, lipid metabolism and pyrimidine metabolism in DKD patients are disordered. CONCLUSIONS: We have identified 5 metabolites and metabolic pathways related to DKD which can serve as biomarkers or targets for disease prevention and drug therapy.

FTO regulates osteoclast development by modulating the proliferation and apoptosis of osteoclast precursors in inflammatory conditions.

Periodontitis is an oral inflammatory disease that causes alveolar bone destruction by activating osteoclast. FTO, a crucial demethylase of N6-methyladenosine(m6A), exerts essential function in maintaining bone homeostasis. However, the effects of FTO on periodontitis-related bone destruction remain unknown. To investigate its role in inflammatory osteoclastogenesis, we overexpressed FTO in osteoclast precursor cells; RNA-seq revealed that differentially expressed genes were mainly enriched in cell cycle, DNA replication, DNA damage response and apoptosis in FTO overexpression cells during RANKL and LPS-stimulated osteoclast differentiation. FTO overexpression upregulated the expression of S phase-related proteins (Cyclin A2, CDK2), and decreased the expression of DNA damage related proteins in osteoclast precursor cells. FTO promoted cell proliferation demonstrated by EdU and CCK8 assay, and reduced apoptotic rate and the expression of apoptosis-related proteins in osteoclast precursor cell. Conversely, FTO inhibitor FB23-2 produced the reverse effect. Mechanistically, FTO overexpression promoted the stability of CyclinA2 and CDK2 mRNA. These results were consistent in m6A binding protein YTHDF2 knockdown cells. Moreover, FB23-2 suppressed osteoclast-related gene expression, osteoclast formation and bone resorption ability. Treatment of FB23-2 reduced the alveolar bone loss in mice of experimental periodontitis. Collectively, our findings revealed that FTO enhanced the mRNA stability and expression of Cyclin A2, CDK2 in a YTHDF2-dependent manner in osteoclast precursor cells, promoted cell proliferation and inhibited cell apoptosis. FB23-2 reduced the formation of osteoclasts, resulted in alleviating the bone destruction in periodontitis mice. These findings indicated that FTO might be the potential target of the treatment of bone loss in periodontitis.

Neutrophil extracellular traps induced by chemotherapy inhibit tumor growth in murine models of colorectal cancer.

Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill cancer cells is unexplored. Here, we report that a combination of glutaminase inhibitor CB-839 and 5-FU inhibited the growth of PIK3CA-mutant colorectal cancers (CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRCs attenuated the efficacy of the drug combination. Moreover, NETs were present in tumor biopsies from patients treated with the drug combination in a phase II clinical trial. Increased NET levels in tumors were associated with longer progression-free survival. Mechanistically, the drug combination induced the expression of IL-8 preferentially in PIK3CA-mutant CRCs to attract neutrophils into the tumors. Further, the drug combination increased the levels of ROS in neutrophils, thereby inducing NETs. Cathepsin G (CTSG), a serine protease localized in NETs, entered CRC cells through the RAGE cell surface protein. The internalized CTSG cleaved 14-3-3 proteins, released BAX, and triggered apoptosis in CRC cells. Thus, our studies illuminate a previously unrecognized mechanism by which chemotherapy-induced NETs kill cancer cells.

Real-world Trends, Rural-urban Differences, and Socioeconomic Disparities in Utilization of Narrow versus Broad Next-generation Sequencing Panels.

Advances in genetic technology have led to the increasing use of genomic panels in precision oncology practice, with panels ranging from a couple to hundreds of genes. However, the clinical utilization and utility of oncology genomic panels, especially among vulnerable populations, is unclear. We examined the association of panel size with socioeconomic status and clinical trial matching. We retrospectively identified 9,886 eligible adult subjects in the Mayo Clinic Health System who underwent genomic testing between January 1, 2016 and June 30, 2020. Patient data were retrieved from structured and unstructured data sources of institutional collections, including cancer registries, clinical data warehouses, and clinical notes. Socioeconomic surrogates were approximated using the Area Deprivation Index (ADI) corresponding to primary residence addresses. Logistic regression was performed to analyze relationships between ADI or rural/urban status and (i) use of genomic test by panel size; (ii) clinical trial matching status. Compared with patients from the most affluent areas, patients had a lower odds of receiving a panel test (vs. a single-gene test) if from areas of higher socioeconomic deprivation [OR (95% confidence interval (CI): 0.71 (0.61-0.83), P < 0.01] or a rural area [OR (95% CI): 0.85 (0.76-0.96), P < 0.01]. Patients in areas of higher socioeconomic deprivation were less likely to be matched to clinical trials if receiving medium panel tests [(OR) (95% CI): 0.69 (0.49-0.97), P = 0.03]; however, there was no difference among patients receiving large panel tests (P > 0.05) and rural patients were almost 2x greater odds of being matched if receiving a large panel test [(OR) (95% CI): 1.76 (1.21-2.55), P < 0.01]. SIGNIFICANCE: We identified socioeconomic and rurality disparities in the use of genomic tests and trial matching by panel size, which may have implications for equal access to targeted therapies. The lack of association between large panel tests and clinical trial matching by socioeconomic status, suggests a potential health equity impact, while removing barriers in access to large panels for rural patients may improve access to trials. However, further research is needed.

METTL3 promotes osteoblast ribosome biogenesis and alleviates periodontitis.

BACKGROUND: Periodontitis is a highly prevalent oral disease characterized by bacterium-induced periodontal inflammation and alveolar bone destruction. Osteoblast function is impaired in periodontitis with a global proteome change. METTL3 is the pivotal methyltransferase of N6-methyladenosine (m6A) that is recently proved to exert a crucial role in osteoblast differentiation. This study aims to investigate the role of METTL3 in osteoblast ribosome biogenesis in periodontitis progression. RESULTS: METTL3 was knocked down in osteoblasts, and the downregulated genes were enriched in ribosome and translation. METTL3 knockdown inhibited ribosome biogenesis and oxidative phosphorylation in LPS-stimulated osteoblasts, whereas METTL3 overexpression facilitated ribosomal and mitochondrial function. Mechanistically, METTL3 mediated osteoblast biological behaviors by activating Wnt/ß-catenin/c-Myc signaling. METTL3 depletion enhanced the mRNA expression and stability of Dkk3 and Sostdc1 via YTHDF2. In periodontitis mice, METTL3 inhibitor SAH promoted alveolar bone loss and local inflammatory status, which were partially rescued by Wnt/ß-catenin pathway activator CHIR-99021 HCl. CONCLUSIONS: METTL3 promoted ribosome biogenesis and oxidative phosphorylation by activating Wnt/ß-catenin/c-Myc signaling in LPS-treated osteoblasts and alleviated the inflammatory alveolar bone destruction in periodontitis mice.

Carbon dots and composite materials with excellent performances in cancer-targeted bioimaging and killing: a review.

Carbon dots (CDs) are nanomaterials with excellent properties, including good biocompatibility, small size, ideal photoluminescence and surface modification, and are becoming one of the most attractive nanomaterials for the imaging, detection and treatment of tumors. Based on these advantages, CDs can be combined other materials to obtain composite particles with improved, even new, performance, mainly in photothermal and photodynamic therapies. This paper reviews the research progress of CDs and their composites in targeted tumor imaging, detection, diagnosis, drug delivery and tumor killing. It also discusses and proposes the challenges and perspectives of their future applications in these fields. This review provides ideas for future applications of novel CD-based materials in the diagnosis and treatment of cancer.

An Integrated Extraction-Purification Process for Raspberry Leaf Polyphenols and Their In Vitro Activities.

To improve the utilization value of raspberry leaves, the extraction and purification conditions of phenolic compounds from raspberry leaves were optimized, and the contents of phenolic compounds and the biological activities of extracts were studied. After steam explosion pretreatment at 115 °C for 15 min, raspberry leaf extract with a total phenolic content (TPC) of 136.30~140.51 mg GAE/g was obtained via homogenization and ultrasound-assisted extraction. In addition, the adsorption relationship between raspberry leaf polyphenols and middle polar XDA-6 macroporous resin was best described by the Langmuir model, and tended to be monolayer adsorption. Its adsorption kinetics best resembled the pseudo second-order kinetic model, and it was speculated that this was influenced by multiple factors. According to the optimal integrated extraction-purification process, the TPC of the extracts increased to 738.98 mg GAE/g after one application of purification and 905.27 mg GAE/g after two applications of purification. Moreover, the latter case showed the highest antioxidant activity and α-glucosidase inhibition activity, and the content of the most typical compound, quercetin-3-glucuronide, reached 199.69 mg/g. SE has a double-edged effect, and is more conducive to the release of active substances as a pre-treatment method. This study provides a theoretical basis for the efficient use of raspberry leaves, further improving their medicinal and economic value.

PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain.

How PD-L1 expression is regulated in cancer is poorly understood. Here, we report that the ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in colorectal cancers (CRCs). ERBB3 is one of the four members of the EGF receptor family, all with protein tyrosine kinase domains. ERBB3 is a pseudokinase with a high binding affinity to ATP. We showed that ERBB3 ATP-binding inactivation mutant reduces tumorigenicity in genetically engineered mouse models and impairs xenograft tumor growth of CRC cell lines. The ERBB3 ATP-binding mutant cells dramatically reduce IFN-γ-induced PD-L1 expression. Mechanistically, ERBB3 regulates IFN-γ-induced PD-L1 expression through the IRS1-PI3K-PDK1-RSK-CREB signaling axis. CREB is the transcription factor that regulates PD-L1 gene expression in CRC cells. Knockin of a tumor-derived ERBB3 mutation located in the kinase domain sensitizes mouse colon cancers to anti-PD1 antibody therapy, suggesting that ERBB3 mutations could be predictive biomarkers for tumors amenable to immune checkpoint therapy.

Lactobacillus johnsonii L531 Ameliorates Salmonella enterica Serovar Typhimurium Diarrhea by Modulating Iron Homeostasis and Oxidative Stress via the IRP2 Pathway.

Salmonella enterica serovar Typhimurium (S. Typhimurium) has evolved mechanisms to evade the host's nutritional immunity and thus promote bacterial growth by using the iron in the host. However, the detailed mechanisms of S. Typhimurium induce dysregulation of iron homeostasis and whether Lactobacillus johnsonii L531 can alleviate the iron metabolism disorder caused by S. Typhimurium has not been fully elucidated. Here, we show that S. Typhimurium activated the expression of iron regulatory protein 2 (IRP2), transferrin receptor 1, and divalent metal transporter protein 1 and suppressed the expression of iron exporter ferroportin, which resulted in iron overload and oxidative stress, inhibiting the key antioxidant proteins NF-E2-related factor 2, Heme Oxygenase-1, and Superoxide Dismutase in vitro and in vivo. L. johnsonii L531 pretreatment effectively reversed these phenomena. IRP2 knockdown inhibited iron overload and oxidative damage induced by S. Typhimurium in IPEC-J2 cells, while IRP2 overexpression promoted iron overload and oxidative damage caused by S. Typhimurium. Interestingly, the protective effect of L. johnsonii L531 on iron homeostasis and antioxidant function was blocked following IRP2 overexpression in Hela cells, demonstrating that L. johnsonii L531 attenuates disruption of iron homeostasis and consequent oxidative damage caused by S. Typhimurium via the IRP2 pathway, which contributes to the prevention of S. Typhimurium diarrhea in mice.

PO2RDF: representation of real-world data for precision oncology using resource description framework.

BACKGROUND: Next-generation sequencing provides comprehensive information about individuals' genetic makeup and is commonplace in precision oncology practice. Due to the heterogeneity of individual patient's disease conditions and treatment journeys, not all targeted therapies were initiated despite actionable mutations. To better understand and support the clinical decision-making process in precision oncology, there is a need to examine real-world associations between patients' genetic information and treatment choices. METHODS: To fill the gap of insufficient use of real-world data (RWD) in electronic health records (EHRs), we generated a single Resource Description Framework (RDF) resource, called PO2RDF (precision oncology to RDF), by integrating information regarding genes, variants, diseases, and drugs from genetic reports and EHRs. RESULTS: There are a total 2,309,014 triples contained in the PO2RDF. Among them, 32,815 triples are related to Gene, 34,695 triples are related to Variant, 8,787 triples are related to Disease, 26,154 triples are related to Drug. We performed two use case analyses to demonstrate the usability of the PO2RDF: (1) we examined real-world associations between EGFR mutations and targeted therapies to confirm existing knowledge and detect off-label use. (2) We examined differences in prognosis for lung cancer patients with/without TP53 mutations. CONCLUSIONS: In conclusion, our work proposed to use RDF to organize and distribute clinical RWD that is otherwise inaccessible externally. Our work serves as a pilot study that will lead to new clinical applications and could ultimately stimulate progress in the field of precision oncology.

Nuclear translocation of p85ß promotes tumorigenesis of PIK3CA helical domain mutant cancer.

PI3Ks consist of p110 catalytic subunits and p85 regulatory subunits. PIK3CA, encoding p110α, is frequently mutated in human cancers. Most PIK3CA mutations are clustered in the helical domain or the kinase domain. Here, we report that p85ß disassociates from p110α helical domain mutant protein and translocates into the nucleus through a nuclear localization sequence (NLS). Nuclear p85ß recruits deubiquitinase USP7 to stabilize EZH1 and EZH2 and enhances H3K27 trimethylation. Knockout of p85ß or p85ß NLS mutant reduces the growth of tumors harboring a PIK3CA helical domain mutation. Our studies illuminate a novel mechanism by which PIK3CA helical domain mutations exert their oncogenic function. Finally, a combination of Alpelisib, a p110α-specific inhibitor, and an EZH inhibitor, Tazemetostat, induces regression of xenograft tumors harboring a PIK3CA helical domain mutation, but not tumors with either a WT PIK3CA or a PIK3CA kinase domain mutation, suggesting that the drug combination could be an effective therapeutic approach for PIK3CA helical domain mutant tumors.

DNMT3A R882 Mutations Confer Unique Clinicopathologic Features in MDS Including a High Risk of AML Transformation.

DNMT3A mutations play a prominent role in clonal hematopoiesis and myeloid neoplasms with arginine (R)882 as a hotspot, however the clinical implications of R882 vs. non-R882 mutations in myeloid neoplasms like myelodysplastic syndrome (MDS) is unclear. By data mining with publicly accessible cancer genomics databases and a clinical genomic database from a tertiary medical institution, DNMT3A R882 mutations were found to be enriched in AML (53% of all DNMT3A mutations) but decreased in frequency in clonal hematopoiesis of indeterminate potential (CHIP) (10.6%) or other myeloid neoplasms including MDS (27%) (p<.001). Next with the largest cohort of patients with DNMT3A R882 mutant MDS known to date from multiple institutions, DNMT3A R882 mutant MDS cases were shown to have more severe leukopenia, enriched SRSF2 and IDH2 mutations, increased cases with excess blasts (47% vs 22.5%, p=.004), markedly increased risk of AML transformation (25.8%, vs. 1.7%, p=.0001) and a worse progression-free survival (PFS) (median 20.3, vs. >50 months, p=.009) than non-R882 mutant MDS cases. DNMT3A R882 mutation is an independent risk factor for worse PFS, and importantly the differences in the risk of AML transformation between R882 vs. non-R882 mutant patients cannot be explained by different treatment approaches. Interestingly the higher risk of AML transformation and the worse PFS in DNMT3A R882 mutant MDS cases are mitigated by coexisting SF3B1 or SRSF2 mutations. The unique clinicopathologic features of DNMT3A R882 mutant MDS shed light on the prognostic and therapeutic implications of DNMT3A R882 mutations.

The Improvement and Clinical Application of Human Oocyte In Vitro Maturation (IVM).

Oocyte in vitro maturation (IVM) is a technology with a long history that was established before IVF. Although it has been studied extensively, the efficiency of IVM has been poor for almost 30 years. In terms of the benefits of IVM, the efficiency and adoption of IVM are being improved by some notable improvements that have occurred in recent years. The establishment of biphasic IVM is the most important advancement in recent years. Biphasic IVM includes the pre-IVM culturing phase and IVM phase. The CNP-mediated pre-IVM culturing system is specifically tailored for non/minimally stimulated immature oocytes, and its efficiency has been shown. This is the most significant improvement made in recent decades in this area. In the clinic, IVM can be used for PCOS patients to avoid the occurrence of ovarian hyperstimulation syndrome (OHSS). Additionally, this method can solve the reproductive problems of some patients with special diseases (resistant ovary syndrome) that cannot be solved by IVF. In most fertility preservation procedures, oocytes in small antral follicles are lost. However, IVM has the ability to capture this kind of oocyte and save reproductive potential. IVM can be easily combined with fertility preservation strategies that have been applied in the clinic and improve the efficiency of fertility preservation. IVM is a useful and attractive technology and may be used widely worldwide in the near future.

Successful ovarian stimulation and pregnancy in an infertile woman with Rathke's cleft cyst: a case report.

PURPOSE: To report a case of successful ovarian stimulation and pregnancy in an infertile woman with Rathke's cleft cyst (RCC). METHODS: This is a case report of a 32-year-old infertile woman with RCC presenting with secondary amenorrhea and hypogonadotropic hypogonadism (HH). Three rounds of ovarian stimulation and ovulation induction by means of HMG and HCG were performed (two before HSG and one after HSG). HSG was performed after two rounds of ovulation induction without pregnancy to assess the fallopian tubes and uterine cavity of the patient. Serum beta-human chorionic gonadotropin (ß-HCG) and ultrasound examination were performed after the third round of ovulation induction to confirm successful pregnancy. RESULTS: HSG revealed that the uterine cavity was normal and that the bilateral fallopian tubes were unobstructed. Four weeks after the third round of ovulation induction, the ß-HCG test was positive (10261 µg/L), and ultrasound examination showed an intrauterine early gestational sac with an embryo (10*7 mm) and a primitive heart tube pulse. CONCLUSIONS: Infertility accompanied by RCC is rare in the clinic. Clarifying the cause of infertility and secondary amenorrhea is very important for achieving a successful pregnancy. This case demonstrates that such infertility can be treated effectively with ovarian stimulation and ovulation induction using HMG and HCG. To the best of our knowledge, this is the first case report of infertility accompanied by RCC.

MiRNA-29c-3p Promotes Intestinal Inflammation via Targeting Leukemia Inhibitory Factor in Ulcerative Colitis.

BACKGROUND: Dysregulation of micro-RNAs (miRNAs) is profoundly linked to inflammatory bowel diseases (IBD), but little is known about the specific biological functions of miRNAs in IBD. This study sought to elucidate the effect and the underlying target of miR-29c-3p in ulcerative colitis (UC). METHODS: The levels of miR-29c-3p and leukemia inhibitory factor (LIF) were measured in inflamed lesions of UC patients and dextran sulfate sodium (DSS)-induced colitis mice by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. MiR-29c-3p was predicted to target LIF by bioinformatics software, which was verified via luciferase reporter assay and transfection of miR-29c-3p mimics or inhibitor. The role of miR-29c-3p/LIF axis in intestinal inflammation was explored in experimental colitis mice and Caco-2 cells. RESULTS: MiR-29c-3p was markedly downregulated while LIF was upregulated in colon tissues of UC patients and DSS-challenged colitis mice as well as in primary intestinal epithelial cells (IECs) and LPS-treated Caco-2 cells. MiR-29c-3p inhibited LIF expression at the transcriptional level via binding to LIF 3'-untranslated region (UTR) in Caco-2 cells. Targeting miR-29c-3p/LIF axis regulated inflammatory cytokines production, cell proliferation and apoptosis. Overexpression of miR-29c-3p aggravated mice experimental colitis via suppressing LIF. CONCLUSION: Our findings demonstrate that the upregulation of miR-29c-3p promotes gut inflammation and the expression of pro-inflammatory mediators via suppressing LIF, thereby modulating the pathogenesis of UC.

Leveraging Genetic Reports and Electronic Health Records for the Prediction of Primary Cancers: Algorithm Development and Validation Study.

BACKGROUND: Precision oncology has the potential to leverage clinical and genomic data in advancing disease prevention, diagnosis, and treatment. A key research area focuses on the early detection of primary cancers and potential prediction of cancers of unknown primary in order to facilitate optimal treatment decisions. OBJECTIVE: This study presents a methodology to harmonize phenotypic and genetic data features to classify primary cancer types and predict cancers of unknown primaries. METHODS: We extracted genetic data elements from oncology genetic reports of 1011 patients with cancer and their corresponding phenotypical data from Mayo Clinic's electronic health records. We modeled both genetic and electronic health record data with HL7 Fast Healthcare Interoperability Resources. The semantic web Resource Description Framework was employed to generate the network-based data representation (ie, patient-phenotypic-genetic network). Based on the Resource Description Framework data graph, Node2vec graph-embedding algorithm was applied to generate features. Multiple machine learning and deep learning backbone models were compared for cancer prediction performance. RESULTS: With 6 machine learning tasks designed in the experiment, we demonstrated the proposed method achieved favorable results in classifying primary cancer types (area under the receiver operating characteristic curve [AUROC] 96.56% for all 9 cancer predictions on average based on the cross-validation) and predicting unknown primaries (AUROC 80.77% for all 8 cancer predictions on average for real-patient validation). To demonstrate the interpretability, 17 phenotypic and genetic features that contributed the most to the prediction of each cancer were identified and validated based on a literature review. CONCLUSIONS: Accurate prediction of cancer types can be achieved with existing electronic health record data with satisfactory precision. The integration of genetic reports improves prediction, illustrating the translational values of incorporating genetic tests early at the diagnosis stage for patients with cancer.

The Relationships between Sleep and Mental and Physical Health of Chinese Elderly: Exploring the Mediating Roles of Diet and Physical Activity.

Sleep quality, diet quality, and physical activity are significant factors influencing physical and mental health. However, few studies have explored their underlying mechanisms, especially among the elderly population in East Asia, where people have food culture and lifestyles distinct from those living in Western countries. Therefore, the current study aimed to explore the relationships among sleep quality, diet quality, physical activity, and physical and mental health in a Chinese elderly sample. Sleep quality, diet quality, physical activity, physical health, and mental health were investigated among 313 Chinese elderly (aged 51-92 years, M = 67.90, SD = 7.94). Mediation analysis was used to examine the empirical model based on previous theories and literature. Close positive relationships were observed between all factors investigated (r = 0.22~0.73, p < 0.001). The relationships between sleep quality and physical and mental health were partially mediated by diet quality and physical activity. In clinical interventions, sleep quality, diet quality, and physical activity can be targeted to improve physical and mental health among the older adult populations.