Family Resilience and Its Influencing Factors in Patients with Stress Urinary Incontinence after Cervical Cancer Surgery: A Retrospective Study.

OBJECTIVE: This study aimed to analyse the family resilience of patients with stress urinary incontinence (SUI) after cervical cancer surgery and its influencing factors. METHODS: Patients with cervical cancer postoperative SUI admitted to our hospital from May 2020, to May 2023, were retrospectively selected. They were divided into low-resilience group and high-resilience group in accordance with the Family Resilience Questionnaire (FaREQ). The general demographic data of the two groups were statistically analysed, and correlation and logistic regression analyses were performed. RESULTS: The FaREQ score of 222 patients was (93.61 ± 8.45). Amongst these patients, 21.62% scored less than 84 points, and 78.38% scored more than 84 points. Significant differences were found in the educational level, indwelling catheter time, family monthly income, religious belief, hope index, psychological resilience, family function and social support between the two groups (p < 0.05). A significant positive correlation was observed between family resilience and the above indicators (p < 0.05). The variance inflation coefficient values of educational level and indwelling catheter time were 15.764 and 43.766, and the tolerance values were 0.063 and 0.023, respectively. After removing them, family monthly income, religious belief, hope index, psychological resilience, family function and social support were the factors affecting the family resilience level of patients with SUI after cervical cancer surgery. CONCLUSIONS: The level of family resilience of patients with SUI after cervical cancer surgery is low. Many factors, such as family monthly income and religious belief, affect the level of resilience. Therefore, corresponding measures could be formulated in advance to improve the level of family resilience of such patients.

Comparing upfront surgery with neoadjuvant treatments in patients with resectable, borderline resectable or locally advanced pancreatic cancer: a systematic review and network meta-analysis of randomized clinical trials.

BACKGROUND: The aim was to explore the optimal neoadjuvant therapy strategy for resectable, borderline resectable, and locally advanced pancreatic cancer, in order to provide a theoretical basis for the development of new neoadjuvant treatment protocols for clinical use. PATIENTS AND METHODS: The authors reviewed literature titles and abstracts comparing three treatment strategies (neoadjuvant chemoradiotherapy, neoadjuvant chemotherapy, and upfront surgery) in PubMed, Embase, The Cochrane Library, Web of Science from 2009 to 2023 to estimate relative odds ratios for resection rate and hazard ratios (HRs) for overall survival (OS) in all include trials. RESULTS: A total of nine studies involving 889 patients were included in the analysis. The treatment methods included upfront surgery, neoadjuvant chemotherapy, and neoadjuvant chemoradiotherapy followed by surgery. The network meta-analysis results demonstrated that neoadjuvant chemoradiotherapy followed by surgery was an effective approach in improving OS for resectable and borderline resectable pancreatic cancer (RPC) patients compared to upfront surgery (HR: 0.79, 95% CI: 0.64-0.98) and neoadjuvant chemotherapy (HR: 0.79, 95% CI: 0.64-0.98). Additionally, neoadjuvant chemoradiotherapy significantly increased the margin negative resection (R0) rate and pathological negative lymph node (pN0) rate in patients with resectable and borderline RPC. However, it is worth noting that neoadjuvant chemoradiotherapy increased the risk of grade 3 or higher treatment-related adverse events, including in patients with locally advanced pancreatic cancer. CONCLUSIONS: The current evidence suggests that neoadjuvant chemoradiotherapy followed by surgery is the optimal choice for treating patients with resectable and borderline RPC. Future research should focus on optimizing neoadjuvant chemoradiotherapy regimens to effectively improve OS while reducing the occurrence of adverse events.

f25, a novel synthetic quinoline derivative, inhibits tongue cancer cell invasion and survival by the PPAR pathway in vitro and vivo.

Tongue cancer has a very high incidence in China, and there is a need to develop new anti-tumour drugs against it. We synthesised 31 novel quinoline derivatives to test their anti-tumour activity. A compound referred to as "f25" was identified through screening for its high in vitro toxicity against an oral squamous carcinoma cell line (CAL-27). f25 exhibited significant cytotoxicity against CAL-27 cells (IC50 = 7.70 ± 0.58 µΜ). f25 also inhibited the migration and invasion of CAL-27 cells to a level comparable with that of the chemotherapy agent cisplatin. Moreover, f25 promoted the apoptosis of CAL-27 cells. Transcriptome sequencing and western blotting showed that the mechanism of action of f25 against CAL-27 cells involved the peroxisome proliferator-activated receptor (PPAR) signalling pathway. Specifically, f25 could bind to PPAR-α, PPAR-ß, and PPAR-γ and increase their expression. In vivo experiments showed that treatment with f25 led to a reduction in tumour volume in nude mice without significant toxicity. Overall, this study highlights the potential of quinoline compounds (particularly f25) for the design and synthesis of anti-tumour drugs. It also underscores the importance of the PPAR signalling pathway as a target for potential cancer therapies.

1-Methylcyclopropene Alleviates Postharvest Chilling Injury of Snap Beans by Enhancing Antioxidant Defense System.

Research background: Chilling injury is a major disorder affecting the quality of tropical and subtropical vegetables during low temperature storage. Snap bean (Phaseolus vulgaris L.) is sensitive to chilling injury. The main purpose of the present study is to investigate the alleviating effects of 1-methylcyclopropene (1-MCP) on chilling injury of snap bean. In addition, the related mechanisms were also detected from the perspective of the changes of antioxidant defense system. Experimental approach: Snap beans were exposed to different volume fractions of 1-MCP. After 24 h of treatment, snap beans were stored at 4 °C for up to 14 days. Chilling injury index, electrolyte leakage, titratable acidity and total soluble solids were determined. Contents of chlorophyll, ascorbic acid and malondialdehyde were assessed. The total antioxidant capacity, Fe(II) ion chelating capacity, scavenging capacities on free radicals and activities of antioxidant enzymes were detected. Total phenol content and activities of related metabolic enzymes were also determined. Results and conclusions: 1-MCP treatment reduced chilling injury index, electrolyte leakage rate and malondialdehyde content of snap beans. The amounts of total soluble solids, titratable acid, ascorbic acid and total chlorophyll in 1-MCP-treated snap beans were significantly higher than those of control. The snap beans treated with 1-MCP showed stronger total antioxidant capacity and metal chelating activity. The 1-MCP treatment enhanced scavenging effects of snap beans on superoxide, hydroxyl and 1,1-diphenyl-2-trinitrophenylhydrazine radicals. The activities of peroxidase, ascorbate peroxidase, superoxide dismutase and catalase in 1-MCP-treated group were higher than of control. The treatment also enhanced the accumulation of phenolic compounds in snap beans by regulating the activities of phenol-metabolizing enzymes such as shikimate dehydrogenase, phenylalanine ammonia lyase enzyme, cinnamic acid 4-hydroxylase and polyphenol oxidase. In conclusion, with the mechanism that involves the activation of enzymatic and non-enzymatic antioxidant systems, 1-MCP has the ability to avoid chilling injury of snap bean. Novelty and scientific contribution: This study gives insights into whether 1-MCP can regulate postharvest cold resistance in vegetables by enhancing the enzymatic antioxidant system and inducing the accumulation of non-enzymatic antioxidants. Considering the results, 1-MCP treatment could be an effective method to alleviate postharvest chilling injury of snap beans during low temperature storage.

Upregulated RPA2 in endometrial tissues of repeated implantation failure patients impairs the endometrial decidualization.

PURPOSE: To investigate the expression and underlying mechanism of RPA2 in endometrium of patients with repeated implantation failure (RIF). METHODS: In this study, we retrieved the expression profiles from GEO databases and filtered the differentially expressed genes between RIF and the fertile control group. Ultimately, RPA2 was confirmed as a target gene. RPA2 expression in endometrial tissues of RIF patients, the control group, and different phases was detected by RT-qPCR, immunohistochemistry, and Western blotting. The role of RPA2 in endometrial decidualization was performed by in vitro decidualization inducing by 8-Br-cAMP and MPA. Furthermore, RT-qPCR was used to detect changes in the decidual biomarkers after transfection of RPA2 overexpression vector in human endometrium stromal cell (HESC). RESULTS: RPA2 was significantly upregulated in the mid-secretory endometrium of patients with RIF. As a proliferation-related gene, RPA2 was obviously higher expressed at proliferative phase during the normal menstrual cycles. Moreover, the downregulation of RPA2 was discovered during decidualization of HESC. Furthermore, RPA2 overexpression impaired decidualization by inhibiting the expression of prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1). CONCLUSIONS: Our finding indicated that aberrant upregulation of RPA2 attenuated decidualization of HESC in RIF women and provided new potential therapeutic targets.

Cancer-associated fibroblasts: tumor defenders in radiation therapy.

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment that are involved in multiple aspects of cancer progression and considered contributors to tumor immune escape. CAFs exhibit a unique radiation resistance phenotype, and can survive clinical radiation doses; however, ionizing radiation can induce changes in their secretions and influence tumor progression by acting on tumor and immune cells. In this review, we describe current knowledge of the effects of radiation therapies on CAFs, as well as summarizing understanding of crosstalk among CAFs, tumor cells, and immune cells. We highlight the important role of CAFs in radiotherapy resistance, and discuss current and future radiotherapy strategies for targeting CAFs.

Dual-Functional Nanoplatform Based on Bimetallic Metal-Organic Frameworks for Synergistic Starvation and Chemodynamic Therapy.

Tumor microenvironment (TME)-responsive chemodynamic therapy (CDT) mediated by nanozymes has been extensively studied in oral squamous cell carcinoma. However, the low catalytic efficiency due to insufficient H2O2 in the TME is still a major challenge for its clinical translation. Herein, we present an antitumor nanoplatform based on a Mn-Co organometallic framework material (MnCoMOF), which shows peroxidase-like (POD-like) activity, loaded with glucose oxidase (GOx@MnCoMOF), demonstrating the ability of H2O2 self-supply and H2O2 conversion to toxic hydroxyl radicals. The encapsulated GOx efficiently catalyzes glucose into gluconic acid and H2O2 at the tumor site, which can cut off the energy supply to inhibit tumor growth and produce a large amount of H2O2 and acid to compensate for their lack in the tumor microenvironment. The POD-like activity of MnCoMOF can convert H2O2 into hydroxyl radicals and eliminate tumor cells. The nanoplatform exhibits enhanced tumor cell cytotoxicity in a high-glucose medium compared with a low-glucose medium, illustrating sufficient generation of H2O2 from glucose by GOx. The in vivo results indicate that GOx@MnCoMOF has excellent antitumor efficacy and can remodel the immune-suppressive tumor microenvironment. In conclusion, the GOx@MnCoMOF nanoplatform possesses dual enzymatic activities, i.e., POD-like and glucose oxidase, to achieve improved tumor-suppressive efficiency through synergistic starvation and chemodynamic therapy, thus providing a new strategy for the clinical treatment of oral cancer.

PCGEM1 promotes cell proliferation and migration in endometriosis by targeting miR-124-3p-mediated ANTXR2 expression.

BACKGROUND: Endometriosis, a common gynaecological disease in women, affects 10% of women of childbearing age. Among infertile women, this proportion is as high as 30-50%. Despite the high prevalence of endometriosis, the pathogenesis of endometriosis is still unclear. METHODS: In the present study, bioinformatics analysis and molecular and animal experiments were employed to explore the functions of PCGEM1 in the pathogenesis of endometriosis. We established an endometriosis rat model and isolated endometrial stromal cells (ESCs) and primary normal ESCs (NESCs). Bioinformatics analysis was adopted to study the roles of PCGEM1 in promoting the pathogenesis of endometriosis. Luciferase reporter assays and RNA pull-down assays were carried out to study the mechanism by which PCGEM1 regulates ANTXR2. RESULTS: Our results indicated that PCGEM1 promoted the motility and proliferation of ectopic endometrial cells, and the underlying mechanism was due to the direct binding of PCGEM1 to miR-124-3p to modulate ANTXR2 expression. CONCLUSION: PCGEM1 can influence endometrial stromal cell proliferation and motility and may be a novel therapeutic target for endometriosis.

Phosphorus removal from wastewater using Ca-modified attapulgite: Fixed-bed column performance and breakthrough curves analysis.

The adsorbent calcium-modified attapulgite (Ca-GAT) prepared by calcium chloride modification and high temperature treatment (700 °C) has proved to remove phosphorus in low-concentration phosphorus wastewater in batch adsorption experiments. Dynamic adsorption performance and industrial application potential still need further determination. This study explored the effects of various parameters on the dynamic phosphorus adsorption, including initial phosphate concentration (2-10 mg/L), flow rate (1-3 mL/min) and adsorption bed height (2-6 cm). Phosphorus adsorption ability improved and the breakthrough time increased with the increase of bed height, flow rate, and a decrease in initial phosphorus concentration. Breakthrough curves fitted four models, the Adams-Bohart, Thomas, Yoon-Nelson and Bed depth service time (BDST). The maximum adsorption amount determined by the Thomas model obtained 13.477 mg/g. The saturated fixed-bed column were regenerated with NaOH, NaOH + NaCl and HCl, among which 0.5 mol/L NaOH had the best regeneration effect. During the utilization of a large fixed-bed to treat the actual membrane bioreactor (MBR) effluent, the breakthrough point (0.5 mg/L) was obtained after 177 h. These results implied that Ca-GAT had an application potential for the treatment of low-concentration phosphorus wastewater (2 mg/L).

Novel tryptanthrin derivatives with benzenesulfonamide substituents: Design, synthesis, and anti-inflammatory evaluation.

Herein, two series of tryptanthrin derivatives with benzenesulfonamide substituents were designed and synthesized to discover novel anti-inflammatory agents. The anti-inflammatory activities of all derivatives were screened by evaluating their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. Among them, compound 8j exhibited the best NO inhibitory activity (IC50 = 1.25 ± 0.21 µM), with no obvious toxicity. Further evaluation showed that 8j could also significantly reduce the levels of pro-inflammatory cytokines interleukin-1ß (IL-1ß, IC50 = 8.48 ± 0.23 µM) and tumor necrosis factor-α (TNF-α, IC50 = 11.53 ± 0.35 µM) and downregulate the LPS-induced expression of iNOS and COX-2. Reverse docking of 8j suggested p38α as the molecular target, which is a well-known crucial player in the p38 MAPK signaling pathway that controls the transcription of pro-inflammatory mediators. Cellular thermal shift assay showed that 8j efficiently stabilized p38α in LPS-treated RAW264.7 cells. Western blot showed that inflammatory response was inhibited by 8j through inhibiting the phosphorylation of p38α and MK2 in the p38 MAPK signaling pathway. Finally, In vivo studies showed that 8j could significantly ameliorate the degree of foot swelling and knee joint pathology in adjuvant-induced arthritis (AIA) rats and reduce levels of TNF-α and IL-1ß in serum, achieving the effect of protecting synovial tissue and ameliorating arthritis. These findings suggested that 8j may be a promising compound for further development of anti-inflammatory agents.

LHX1 as a potential biomarker regulates EMT induction and cellular behaviors in uterine corpus endometrial carcinoma.

OBJECTIVES: To investigate the expression of LHX1 and its role as a biomarker in the diagnosis and prognosis of Uterine Corpus Endometrial Carcinoma (UCEC). METHODS: The Cancer Genome Atlas (TCGA) database was used to detect the expression level of LHX1 in UCEC cells and tissues, and to find out the effect of LHX1 on prognosis. Co-expressed genes were then identified by Spearman correlation analysis, and the protein-protein interaction network was constructed using Cytoscape software. The R "clusterProfiler" package was used to conduct Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A series of in vitro experiments were performed to evaluate LHX1 expression and detect UCEC cell proliferation, invasion, and migration. Western blotting was used to determine the effect of LHX1 on expression levels of Epithelial-Mesenchymal Transition (EMT)-related proteins. RESULTS: LHX1 was upregulated in UCEC tissues and correlated with poor overall survival and disease-specific survival outcomes. Functional enrichment analysis suggested that genes co-expressed with LHX1 were enriched in cell adhesion. The expression of LHX1 was positively correlated with the expression levels of genes related to EMT induction and invasion. LHX1 can enhance the proliferation, migration, and invasion activities of UCEC cells in vitro, and alter the expression levels of EMT-related proteins. CONCLUSION: LHX1 expression was highly upregulated in UCEC cells and tissues, which was correlated with the prognosis of patients with UCEC. LHX1 may regulate UCEC progression at least in part by modulating EMT induction.

Epothilone D Modulates Autism-like Behaviors in the BTBR Mouse Model of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by impaired social communication, abnormal repetitive behaviors and restricted interests and/or sensory behaviors. It has been widely accepted that ASD involves a complex interplay of both genetic and environmental risk factors. Existing medications are only symptomatic treatments, there are no effective treatments that can improve these core social behavior deficits. Recent studies indicated that synaptic development and abnormal myelination are linked to the pathogenesis of ASD. The stable tubule only polypeptide (STOP) protein, also known as microtubule-associated protein 6, plays an important role in neuronal development and synaptic plasticity. Our previous studies showed that STOP protein was significantly reduced in the plasma of autistic subjects and in the cortex of BTBR T+ Itpr3tf (BTBR) mouse model of ASD. Furthermore, studies have shown that Epothilone D, a taxol-like microtubule-stabilizing agent, could alleviate behavioral and synaptic deficits in STOP-null mice. Here, we further evaluate whether Epothilone D treatment is sufficient to modulate the autism-like behaviors in the BTBR mice, and explore the underlying mechanism. BTBR mice were treated either with Epothilone D dissolved in 99% dimethyl sulfoxide (DMSO) or with 99% DMSO vehicle. Our studies demonstrated that the restricted and repetitive behaviors of BTBR mice were improved after Epothilone D treatment, which could be achieved by improving microtubule stability and further regulating the expression of excitatory synapse-related and myelin-related proteins. These results indicate that microtubule stability may be a new and promising therapeutic target for treating patients with ASD.

LHX1 as a potential biomarker regulates EMT induction and cellular behaviors in uterine corpus endometrial carcinoma

Abstract Objectives: To investigate the expression of LHX1 and its role as a biomarker in the diagnosis and prognosis of Uterine Corpus Endometrial Carcinoma (UCEC). Methods: The Cancer Genome Atlas (TCGA) database was used to detect the expression level of LHX1 in UCEC cells and tissues, and to find out the effect of LHX1 on prognosis. Co-expressed genes were then identified by Spearman correlation analysis, and the protein-protein interaction network was constructed using Cytoscape software. The R "clusterProfiler" package was used to conduct Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A series of in vitro experiments were performed to evaluate LHX1 expression and detect UCEC cell proliferation, invasion, and migration. Western blotting was used to determine the effect of LHX1 on expression levels of Epithelial-Mesenchymal Transition (EMT)-related proteins. Results: LHX1 was upregulated in UCEC tissues and correlated with poor overall survival and disease-specific survival outcomes. Functional enrichment analysis suggested that genes co-expressed with LHX1 were enriched in cell adhesion. The expression of LHX1 was positively correlated with the expression levels of genes related to EMT induction and invasion. LHX1 can enhance the proliferation, migration, and invasion activities of UCEC cells in vitro, and alter the expression levels of EMT-related proteins. Conclusion: LHX1 expression was highly upregulated in UCEC cells and tissues, which was correlated with the prognosis of patients with UCEC. LHX1 may regulate UCEC progression at least in part by modulating EMT induction.

The Prebiotic Effects of Oats on Blood Lipids, Gut Microbiota, and Short-Chain Fatty Acids in Mildly Hypercholesterolemic Subjects Compared With Rice: A Randomized, Controlled Trial.

Phytochemicals derived from oats are reported to possess a beneficial effect on modulating dyslipidemia, specifically on lowering total and LDL cholesterol. However, deeper insights into its mechanism remain unclear. In this randomized controlled study, we assigned 210 mildly hypercholesterolemic subjects from three study centers across China (Beijing, Nanjing, and Shanghai) to consume 80 g of oats or rice daily for 45 days. Plasma lipid profiles, short chain fatty acids (SCFAs), and fecal microbiota were measured. The results showed that total cholesterol (TC) and non-high-density lipoprotein cholesterol (non-HDL-C) decreased significantly with both oats and rice intake after 30 and 45 days. The reduction in TC and non-HDL-C was greater in the participants consuming oats compared with rice at day 45 (p = 0.011 and 0.049, respectively). Oat consumption significantly increased the abundance of Akkermansia muciniphila and Roseburia, and the relative abundance of Dialister, Butyrivibrio, and Paraprevotella, and decreased unclassified f-Sutterellaceae. In the oat group, Bifidobacterium abundance was negatively correlated with LDL-C (p = 0.01, r = -0.31) and, TC and LDL-C were negatively correlated to Faecalibacterium prausnitzii (p = 0.02, r = -0.29; p = 0.03, r = -0.27, respectively). Enterobacteriaceae, Roseburia, and Faecalibacterium prausnitzii were positively correlated with plasma butyric acid and valeric acid concentrations and negatively correlated to isobutyric acid. HDL-C was negatively correlated with valeric acid (p = 0.02, r = -0.25) and total triglyceride (TG) was positively correlated to isovaleric acid (p = 0.03, r = 0.23). Taken together, oats consumption significantly reduced TC and LDL-C, and also mediated a prebiotic effect on gut microbiome. Akkermansia muciniphila, Roseburia, Bifidobacterium, and Faecalibacterium prausnitzii, and plasma SCFA correlated with oat-induced changes in plasma lipids, suggesting prebiotic activity of oats to modulate gut microbiome could contribute towards its cholesterol-lowering effect.

Construction of MOF-shell porous materials and performance studies in the selective adsorption and separation of benzene pollutants.

Metastable Cu2O is an attractive material for the architectural design of integrated nanomaterials. In this context, Cu2O was used as the sacrificial agent to form the core-shell structure of Cu2O@HKUST-1 by in situ growth technology. The MOFs with BOPs adsorption property were gathered together by a Cu2O etching method, and the hollow structure of the HKUST-1 shell material with fast BOP adsorption was successfully constructed. The adsorption experiments showed that the HKUST-1 shell has a good adsorption effect on nitrobenzene pollutants in wastewater. The investigation of various factors affecting the adsorption, thermodynamic and kinetic equations was carried out. The adsorption equilibrium was reached within 30 min, and the maximum adsorption capacity was 94.67 mg g-1 at 298 K. The adsorption capacity of nitrobenzene by the HKUST-1 shell is in good agreement with the Freundlich model and the second-order kinetic model. The possible mechanism of adsorption of nitrobenzene by the HKUST-1 shell was discussed. The experimental results suggested that Cu-BTC materials have potential applications for wastewater treatment involving benzene pollutants.

Genetic features and efficacy of decitabine-based chemotherapy in elderly patients with acute myeloid leukemia.

OBJECTIVES: The outcome of elderly acute myeloid leukemia (AML) patients is poor, which was traditionally attributed to patient- and leukemia-related factors. However, studies about the genetic features of these elderly patients have not been integrated and the genetic mechanism of their poor outcome is less known. METHODS: Here, we used next generation sequencing (NGS) to identify the genetic features of elderly AML patients and confirmed the efficacy of chemotherapy based on molecular aberrations. Mutations in 111 genes relevant to hematological malignancy was analysed by virtue of NGS and the genetic differences were compared between elderly (n=52) and young (n=161) AML patients. Furthermore, the outcome of decitabine-based chemotherapy was identified in elderly patients. RESULTS: Frequencies of adverse genetic alterations, such as RUNX1 and secondary-type mutations (ASXL1, STAG2 and spliceosome), were much higher in elderly patients, while the frequency of WT1 mutations was much lower. Moreover, epigenetic mutations such as DNMT3A, TET2, ASXL1 and IDH2, were also more common in elderly patients. Furthermore, there were 39 elderly patients receiving the decitabine-based chemotherapy, and the results showed that the overall response rate (ORR) and complete remission rate (CR) were 76.9% and 71.8%, respectively. The median overall survival (OS) for those older patients was 12 months, and the 2-year OS probability was 20.5%. DISCUSSION: Our study provides deep understanding into the molecular mechanisms of the poor outcome of elderly AML patients. CONCLUSION: Epigenetic mutations play an important role, and decitabine-based regimen can be used as alternative first-line chemotherapy for elderly patients.

Profiling of somatic mutations and fusion genes in acute myeloid leukemia patients with FLT3-ITD or FLT3-TKD mutation at diagnosis reveals distinct evolutionary patterns.

BACKGROUND: The receptor tyrosine kinase FLT3 with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) is a poor prognostic factor; however, the prognostic significance of missense mutation in the tyrosine kinase domain (FLT3-TKD) is controversial. Furthermore, the accompanying mutations and fusion genes with FLT3 mutations are unclear in acute myeloid leukemia (AML). METHODS: We investigated FLT3 mutations and their correlation with other gene mutations and gene fusions through two RNA-seq based next-generation sequencing (NGS) method and prognostic impact in 207 de novo AML patients. RESULTS: FLT3-ITD mutations were positive in 58 patients (28%), and FLT3-TKD mutations were positive in 20 patients (9.7%). FLT3-ITD was associated with a higher white blood cell count (WBC, mean 72.9 × 109/L vs. 24.2 × 109/L, P = 0.000), higher bone marrow blasts (mean 65.9% vs. 56.0%, P = 0.024), and NK-AML (normal karyotype) (64.8% vs. 48.4%, P = 0.043). NPM1 and DNMT3A mutations were enriched in FLT3-ITD (53.5% vs. 15.3%, P = 0.000; 34.6% vs. 13%, P = 0.003). However, the mutations of CEBPA were excluded in FLT3-AML (3.8% vs. 0% vs. 19.8%, P = 0.005). Mutations of Ras and TP53 were unlikely associated with FLT3-ITD (1.9% vs. 20.6%, P = 0.006; 0% vs. 6.1%, P = 0.04). The common fusion genes (> 10%) in FLT3-ITD had MLL-rearrangement and NUP98-rearrangement, while the common fusion genes in FLT3-TKD had AML1-ETO and MLL-rearrangement. Two novel fusion genes PRDM16-SKI and EFAN2-ZNF238 were identified in FLT3-ITD patients. Gene fusions and NPM1 mutation were mutually excluded in FLT3-ITD and FLT3-TKD patients. Their patterns of mutual exclusivity and cooperation among mutated genes suggest that additional driver genetic alterations are required and reveal two evolutionary patterns of FLT3 pathogenesis. Patients with FLT3-ITD had a lower CR (complete remission) rate, lower 3-year OS (overall survival), DFS (disease-free survival), and EFS (event-free survival) compared to FLT3wtAML. NK-AML with FLT3-ITD had a lower 3-year OS, DFS, and EFS than those without, while FLT3-TKD did not influence the survival in whole cohort and NK-AML. Besides, we found that FLT3-ITD/TET2 bimutation defined a poor prognostic subgroup. CONCLUSIONS: Our study offers deep insights into the molecular pathogenesis and biology of AML with FLT3-ITD and FLT3-TKD by providing the profiles of concurrent molecular alterations and the clinical impact of FLT3-ITD and FLT3-TKD on AML patients.

Effects of a preoperative forced-air warming system for patients undergoing video-assisted thoracic surgery: A randomized controlled trial.

BACKGROUND: The incidence of intraoperative hypothermia is still high despite the proposal of different preventive measures during thoracoscopic surgery. This randomized control study evaluated the effects of 30-minute prewarming combined with a forced-air warming system during surgery to prevent intraoperative hypothermia in patients undergoing video-assisted thoracic surgery under general anesthesia combined with erector spinae nerve block. METHODS: Ninety-eight patients were randomly and equally allocated to prewarming or warming groups (n = 49 each). The primary outcome was the incidence of intraoperative hypothermia. Secondary outcomes were core temperature, irrigation and infused fluid, estimated blood loss, urine output, type of surgery, intraoperative anesthetic dosage, hemodynamics, recovery time, the incidence of postoperative shivering, thermal comfort, postoperative sufentanil consumption and pain intensity, patient satisfaction, and adverse events. RESULTS: The incidence of intraoperative hypothermia was significantly lower in the prewarming group than the warming group (12.24% vs 32.65%, P = .015). Core temperature showed the highest decrease 30 minutes after surgery start in both groups; however, the rate was lower in the prewarming than in the warming group (0.31 ±â€Š0.04°C vs 0.42 ±â€Š0.06°C, P < .05). Compared with the warming group, higher core temperatures were recorded for patients in the prewarming group from T1 to T6 (P < .05). Significantly fewer patients with mild hypothermia were in the prewarming group (5 vs 13, P = .037) and recovery time was significantly reduced in the prewarming group (P < .05). Although the incidence of postoperative shivering was lower in the prewarming group, it was not statistically significant (6.12% vs 18.37%, P = .064). Likewise, the shivering severity was similar for both groups. Thermal comfort was significantly increased in the prewarming group, although patient satisfaction was comparable between the 2 groups (P > .05). No adverse events occurred associated with the forced-air warming system. Both groups shared similar baseline demographics, type of surgery, total irrigation fluid, total infused fluid, estimated blood loss, urine output, intraoperative anesthetic dosage, hemodynamics, duration of anesthesia and operation time, postoperative sufentanil consumption, and pain intensity. CONCLUSION: In patients undergoing video-assisted thoracic surgery, prewarming for 30 minutes before the induction of anesthesia combined with a forced-air warming system may improve perioperative core temperature and the thermal comfort, although the incidence of postoperative shivering and severity did not improve.

A novel TSC2 c.4511 T > C missense variant associated with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal-dominant hereditary disease characterized by hamartomas of multiple organ systems, including the brain, skin, heart, kidney and lung. Genetically, TSC is caused by pathogenic variants in the TSC1 or TSC2 gene. CASE PRESENTATION: We reported a sporadic case of a 32-year-old Han Chinese male diagnosed with TSC, whose spouse had a history of two spontaneous miscarriages and an induced abortion of a 30-week fetus identified with cardiac rhabdomyoma by ultrasound. A novel heterozygous missense variant in the TSC2 gene (Exon35:c.4511 T > C:p.L1504P) was identified in the male patient and the aborted fetus by next-generation sequencing, but not in his wife or both his parents. According to the ACMG/AMP criteria, this variant was classified as a "likely pathogenic" variant. CONCLUSION: The novel TSC2:c.4511 T > C variant identified was highly likely associated with TSC and could potentially lead to adverse reproductive outcomes. IVF-ET and pre-implantation genetic diagnosis for TSC are recommended for this patient in the future to prevent fetal TSC.