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Background: Currently, chemotherapy plus immunotherapy followed by maintenance therapy with immune monotherapy is the preferred first-line treatment option for extensive-stage small cell lung cancer (ES-SCLC), but with limited overall survival (OS) and progression-free survival (PFS) benefits. The combination of anti-angiogenic drugs with immunotherapy has shown encouraging anti-tumor activity and tolerability, with some degree of overcoming immune resistance. This study aimed to evaluate the effectiveness and safety of anlotinib plus anti-programmed cell death 1/ligand 1 (anti-PD-1/PD-L1) antibodies as maintenance therapy after first-line chemotherapy combined with immunotherapy in ES-SCLC. Methods: Between June 2020 and December 2021, 12 patients with newly diagnosed ES-SCLC in the First Affiliated Hospital of Army Medical University were retrospectively analyzed. All patients without disease progression after 4-6 cycles of first-line platinum-containing chemotherapy plus anti-PD-1/PD-L1 antibodies received anlotinib (12 mg oral/day, days 1-14, followed by 1 week off, every 3 weeks per cycle) plus anti-PD-1/PD-L1 antibodies as maintenance therapy. Several patients underwent chest radiotherapy (intensity-modulated radiotherapy using a 6 MV X-ray) without disease progression before maintenance therapy. The effectiveness and safety of anlotinib plus anti-PD-1/PD-L1 antibodies as maintenance therapy after first-line chemotherapy combined with immunotherapy in ES-SCLC were evaluated. Results: The median follow-up time was 31.1 months. During first-line treatment (including maintenance therapy), one patient achieved a complete response, eight patients achieved a partial response (PR), and three patients had stable disease, with an objective response rate of 75.0% and a disease control rate of 100.0%. During maintenance therapy with anlotinib plus anti-PD-1/PD-L1 antibodies, 50.0% of patients achieved further lesion remission on the basis of the prior initial treatment, of which one patient achieved a PR. The median PFS was 13.6 [95% confidence interval (CI): 11.2-15.6] months, and the median OS was 19.5 (95% CI: 14.5-24.5) months. Treatment-related any grade and grade 3-4 adverse events (AEs) were reported in 100.0% and 58.3% of patients, respectively. No life-threatening AEs were observed. Grade 3-4 AEs included leukocytopenia (58.3%, 7/12), thrombocytopenia (33.3%, 4/12), nausea (33.3%, 4/12), anemia (16.7%, 2/12), and fatigue (8.3%, 1/12). All AEs during maintenance therapy were tolerated and were regarded as grade 1-2, with the majority being fatigue, nausea, rash, and hemoptysis. Conclusions: The combination of anlotinib with anti-PD-1/PD-L1 antibodies demonstrated encouraging effectiveness and safety in treating patients with ES-SCLC, suggesting that it may be a preferred option for maintenance therapy after first-line chemotherapy combined with immunotherapy.
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BACKGROUND: Alport syndrome (AS) is an inherited nephropathy caused by mutations in the type IV collagen genes. It is clinically characterized by damage to the eyes, ears and kidneys. Diagnosis of AS is hampered by its atypical clinical picture, particularly when the typical features, include persistent hematuria and microscopic changes in the glomerular basement membrane (GBM), are the only clinical manifestations in the patient. METHODS: We screened 10 families with suspected AS using whole exome sequencing (WES) and analyzed the harmfulness, conservation, and protein structure changes of mutated genes. In further, we performed in vitro functional analysis of two missense mutations in the COL4A5 gene (c.2359G > C, p.G787R and c.2605G > A, p.G869R). RESULTS: We identified 11 pathogenic variants in the type IV collagen genes (COL4A3, COL4A4 and COL4A5). These pathogenic variants include eight missense mutations, two nonsense mutations and one frameshift mutation. Notably, Family 2 had digenic mutations in the COL4A3 (p.G1170A) and UMOD genes (p.M229K). Family 3 had a digenic missense mutation (p.G997E) in COL4A3 and a frameshift mutation (p.P502L fs*151) in COL4A4. To our knowledge, four of the 11 mutations are novel mutations. In addition, we found that COL4A5 mutation relation mRNA levels were significantly decreased in HEK 293 T cell compared to control, while the cellular localization remained the same. CONCLUSIONS: Our research expands the spectrum of COL4A3-5 pathogenic variants, which is helpful for clinical and scientific research.
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Autoantígenos , Colágeno Tipo IV , Nefritis Hereditaria , Linaje , Humanos , Nefritis Hereditaria/genética , Nefritis Hereditaria/patología , Colágeno Tipo IV/genética , Autoantígenos/genética , Femenino , Masculino , Adulto , Mutación , Secuenciación del Exoma , Persona de Mediana Edad , Mutación Missense , Células HEK293RESUMEN
BACKGROUND: Germline mutations have been identified in a small number of hereditary cancers, but the genetic predisposition for many familial cancers remains to be elucidated. METHODS: This study identified a Chinese pedigree that presented different cancers (breast cancer, BRCA; adenocarcinoma of the esophagogastric junction, AEG; and B-cell acute lymphoblastic leukemia, B-ALL) in each of the three generations. Whole-genome sequencing and whole-exome sequencing were performed on peripheral blood or bone marrow and cancer biopsy samples. Whole-genome bisulfite sequencing was conducted on the monozygotic twin brothers, one of whom developed B-ALL. RESULTS: According to the ACMG guidelines, bioinformatic analysis of the genome sequencing revealed 20 germline mutations, particularly mutations in the DNAH11 (c.9463G > A) and CFH (c.2314G > A) genes that were documented in the COSMIC database and validated by Sanger sequencing. Forty-one common somatic mutated genes were identified in the cancer samples, displaying the same type of single nucleotide substitution Signature 5. Meanwhile, hypomethylation of PLEK2, MRAS, and RXRA as well as hypermethylation of CpG island associated with WT1 was shown in the twin with B-ALL. CONCLUSIONS: These findings reveal genomic alterations in a pedigree with multiple cancers. Mutations found in the DNAH11, CFH genes, and other genes predispose to malignancies in this family. Dysregulated methylation of WT1, PLEK2, MRAS, and RXRA in the twin with B-ALL increases cancer susceptibility. The similarity of the somatic genetic changes among the three cancers indicates a hereditary impact on the pedigree. These familial cancers with germline and somatic mutations, as well as epigenomic alterations, represent a common molecular basis for many multiple cancer pedigrees.
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Metilación de ADN , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Linaje , Humanos , Masculino , Femenino , Secuenciación Completa del Genoma , Persona de Mediana Edad , Genómica/métodos , Adulto , Epigénesis Genética , Islas de CpG , Epigenómica/métodos , Dineínas Axonemales/genéticaRESUMEN
OBJECTIVE: To explore the effect and mechanism of relaxin (RLX) in the growth and metastasis of livercancer after combination treatment with transarterial chemoembolization (TACE). MATERIALS AND METHODS: HCCLM3 and Huh-7 cells were adopted to evaluate the effect of tumor proliferation, migration, and invasion after RLX administration in vitro. The rabbit VX2 model was used to evaluate the biosafety, doxorubicin penetration, local tumor response, tumor metastasis, and survival benefit of RLX combined with TACE treatment. RESULTS: RLX did not affect the proliferation, migration, or invasion of HCCLM3 and Huh-7 cells, and the expression of E-cadherin and HIF-1α also remained unchanged while the MMP-9 protein was upregulated in vitro. In the rabbit VX2 model, compared to the normal saline group (NS), RLX group (RLX) and TACE mono-therapy group (TACE), the group that received TACE combined with RLX (TACE + RLX) showed an improved local tumor response and survival benefit. Furthermore, TACE combined with RLX was found to reduce tumor metastasis. This combination therapy reduced the fibrotic extracellular matrix in the tumor microenvironment, allowing for better penetration of doxorubicin, improved infiltration of CD8+ T cells and affected the secretion of cytokines. Additionally, RLX combined with TACE was able to decrease the expression of HIF-1α and PD-L1. The biosafety of TACE combined with RLX was also confirmed. CONCLUSION: RLX synergized with TACE by mitigating the fibrotic extracellular matrix and tumor hypoxic microenvironment, improving the therapeutic effect and inhibiting metastasis during the treatment of liver cancer.
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Quimioembolización Terapéutica , Neoplasias Hepáticas , Relaxina , Animales , Quimioembolización Terapéutica/métodos , Conejos , Relaxina/administración & dosificación , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Humanos , Terapia Combinada , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Metástasis de la NeoplasiaRESUMEN
Background: Diabetic kidney disease (DKD) is an intricate complication of diabetes with limited treatment options. Anoikis, a programmed cell death activated by loss of cell anchorage to the extracellular matrix, participated in various physiological and pathological processes. Our study aimed to elucidate the role of anoikis-related genes in DKD pathogenesis. Methods: Differentially expressed genes (DEGs) associated with anoikis in DKD were identified. Weighted gene co-expression network analysis (WGCNA) was conducted to identify DKD-correlated modules and assess their functional implications. A diagnostic model for DKD was developed using LASSO regression and Gene set variation analysis (GSVA) was performed for enrichment analysis. Experimental validation was employed to validate the significance of selected genes in the progression of DKD. Results: We identified 10 anoikis-related DEGs involved in key signaling pathways impacting DKD progression. WGCNA highlighted the yellow module's significant enrichment in immune response and regulatory pathways. Correlation analysis further revealed the association between immune infiltration and anoikis-related DEGs. Our LASSO regression-based diagnostic model demonstrated a well-predictive efficacy with seven identified genes. GSVA indicated that gene function in the high-risk group was primarily associated with immune regulation. Further experimental validation using diabetic mouse models and data analysis in the single-cell dataset confirmed the significance of PYCARD and SFN in DKD progression. High glucose stimulation in RAW264.7 and TCMK-1 cells showed significantly increased expression levels of both Pycard and Sfn. Co-expression analysis demonstrated distinct functions of PYCARD and SFN, with KEGG pathway analysis showing significant enrichment in immune regulation and cell proliferation pathway. Conclusion: In conclusion, our study provides valuable insights into the molecular mechanisms involved in DKD pathogenesis, specifically highlighting the role of anoikis-related genes in modulating immune infiltration. These findings suggest that targeting these genes may hold promise for future diagnostic and therapeutic approaches in DKD management.
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Blackberry polysaccharides with certain molecular weight distribution have good bioactivity. In this research, type 2 diabetes mice were used to investigate the hypoglycemic effect of blackberry polysaccharides with three different molecular weights, BBP (603.59 kDa), BBP-8 (408.13 kDa) and BBP-24 (247.62 kDa), through gut microbiota modulation. Blackberry polysaccharides exhibited stronger hypoglycemic activity after degradation, and the FBG of BBP, BBP-8 and BBP-24 was reduced to 20.21 ± 4.17 mmol L-1, 20.6 ± 7.23 mmol L-1 and 17.32 ± 6.59 mmol L-1 and OGTT-AUC was reduced by 14.76%, 19.80% and 25.04%, respectively, after 8-week intervention. Furthermore, 16S rRNA gene sequencing analysis indicated that BBP, BBP-8 and BBP-24 could reshape the diversity and composition of the gut microbiota. From 0 to 4 weeks, the F/B of BBP, BBP-8 and BBP-24 reduced by 56.44%, 47.19% and 62.04%, reaching 3.39, 6.54, and 3.11 in the 8th week, respectively, which suggested the faster utilization of BBP-24. Moreover, the intervention the three blackberry polysaccharides increased the relative abundance of the targeted beneficial bacteria Oscillospira and Bacteroidaceae Bacteroides and decreased the relative abundance of the pathogenic bacterium Allobaculum. In general, the result demonstrated that blackberry polysaccharides with a lower molecular weight are more easily fermented, making the theoretical basis for the development of blackberry polysaccharides as a probiotic food to rapidly regulate intestinal flora for type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Hipoglucemiantes , Peso Molecular , Polisacáridos , Rubus , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Polisacáridos/farmacología , Polisacáridos/química , Ratones , Hipoglucemiantes/farmacología , Masculino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Rubus/química , Glucemia/metabolismo , Bacterias/clasificación , Bacterias/genética , Bacterias/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Extractos Vegetales/farmacologíaRESUMEN
The hypothalamic-pituitary-gonadal axis (HPG) is the key neuroendocrine axis involved in reproductive regulation. Brain and muscle ARNT-like protein 1 (Bmal1) participates in regulating the metabolism of various endocrine hormones. However, the regulation of Bmal1 on HPG and female fertility is unclear. This study aims to explore the regulation of female reproduction by Bmal1 via the HPG axis in mice. Bmal1-knockout (Ko) mice were generated using the CRISPR/Cas9 technology. The structure, function, and estrous cycle of ovarian in Bmal1 Ko female mice were measured. The key genes and proteins of the HPG axis involved in regulating female reproduction were examined through transcriptome analysis and then verified by RT-PCR, immunohistochemistry, and western blot. Furthermore, the fertility of female mice was detected after intervening prolactin (PRL) and progesterone (Pg) in Bmal1 ko mice. The number of offspring and ovarian weight were significantly lower in Bmal1-Ko mice than in wild-type (Wt) mice. In Bmal1-Ko mice, ovarian cells were arranged loosely and irregularly, and the total number of follicles was significantly reduced. No corpus luteum was found in the ovaries. Vaginal smears revealed that Bmal1-Ko mice had an irregular estrus cycle. In Bmal1-Ko mice, Star expression was decreased, PRL and luteinizing hormone (LH) levels were increased, and dopamine (DA) and Pg levels were decreased. Inhibition of PRL partially recovered the estrous cycle, corpus luteum formation, and Star expression in the ovaries. Pg supplementation promoted embryo implantation in Bmal1-Ko female mice. Bmal1 Ko increases serum PRL levels in female mice likely by reducing DA levels, thus affecting luteal formation, resulting in decreased Star expression and Pg production, hindering female reproduction. Inhibition of PRL or restoration of Pg can partially restore reproductive capacity in female Bmal1-Ko mice. Thus, Bmal1 may regulate female reproduction via the HPG axis in mice, suggesting that Bmal1 is a potential target to treat female infertility.
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Factores de Transcripción ARNTL , Sistema Hipotálamo-Hipofisario , Ovario , Reproducción , Animales , Femenino , Ratones , Factores de Transcripción ARNTL/metabolismo , Factores de Transcripción ARNTL/genética , Ciclo Estral , Fertilidad , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Ovario/metabolismo , Progesterona/metabolismo , Prolactina/metabolismoRESUMEN
PURPOSE: To evaluate the effect of the school curriculum and on-site observation of interventional radiology (IR) operations in clinics on undergraduates' radiation anxiety, interest, and career intention. METHODS: Between the academic years 2021 and 2023, all of the fourth-year undergraduates were surveyed by questionnaires, which covered their pre-curriculum, post-curriculum in-school, and post-on-site view of IR surgeries in clinic. The survey included categories of gender, fear of X-ray and IR operation, interest in IR surgery, and career-pursuing intention. RESULTS: A total of 333 (91.0%) respondents (111 students for three times) were included in analyses. The fear of X-ray and radiation exposure during IR procedures was reduced after taking school courses (p < 0.001), and it was further decreased after on-site viewing (p < 0.001). The association values among the three groups were 33.8% and 41.9%, respectively. The interest in IR was improved both after applying for the curriculum and after clinical exposure to IR surgery (p < 0.001). In addition, 4 (3.6%) and 12 (10.8%) students showed a sense of achievement after taking courses and on-site viewing, respectively. The association value was 49.4%. Regarding career intention, it was both significantly increased after taking courses and on-site observation (p < 0.001). Besides, 8 (7.2%), 17 (15.3%), and 36 (32.4%) students in the three groups considered IR as the preferred career choice, respectively. CONCLUSIONS: Applying for IR curriculum could reduce undergraduates' radiation anxiety, and activate their professional interest and career pursuing intention. Clinical exposure to IR surgeries further boosted this effect. CLINICAL RELEVANCE STATEMENT: Educational interventions of curriculum and on-site view of IR surgery improve the undergraduates' interest in IR and stimulate their career intention, which is crucial for the advancement of IR. KEY POINTS: Increasing interest in interventional radiology (IR) as a career is urgent, given rising demand of services. Education and on-site viewing of IR surgery reduced radiation anxiety and increased interest in IR. Early exposure to IR is effective at encouraging undergraduates to consider IR as their career.
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Fabry disease, a lysosomal storage disease, is an uncommon X-linked recessive genetic disorder stemming from abnormalities in the alpha-galactosidase gene (GLA) that codes human alpha-Galactosidase A (α-Gal A). To date, over 800 GLA mutations have been found to cause Fabry disease (FD). Continued enhancement of the GLA mutation spectrum will contribute to a deeper recognition and underlying mechanisms of FD. In this study, a 27-year-old male proband exhibited a typical phenotype of Fabry disease. Subsequently, family screening for Fabry disease was conducted, and high-throughput sequencing was employed to identify the mutated gene. The three-level structure of the mutated protein was analyzed, and its subcellular localization and enzymatic activity were determined. Apoptosis was assessed in GLA mutant cell lines to confirm the functional effects. As a result, a new mutation, c.777_778del (p. Gly261Leufs*3), in the GLA gene was identified. The mutation caused a frameshift during translation and the premature appearance of a termination codon, which led to a partial deletion of the domain in C-terminal region and altered the protein's tertiary structure. In vitro experiments revealed a significant reduction of the enzymatic activity in mutant cells. The expression was noticeably decreased at the mRNA and protein levels in mutant cell lines. Additionally, the subcellular localization of α-Gal A changed from a homogeneous distribution to punctate aggregation in the cytoplasm. GLA mutant cells exhibited significantly higher levels of apoptosis compared to wild-type cells.
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Codón sin Sentido , Enfermedad de Fabry , Linaje , alfa-Galactosidasa , Humanos , Enfermedad de Fabry/genética , Enfermedad de Fabry/diagnóstico , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismo , Masculino , Adulto , China , Pueblo Asiatico/genética , Apoptosis/genética , Pueblos del Este de AsiaRESUMEN
In this study, blackberry polysaccharide-selenium nanoparticles (BBP-24-3Se) were first prepared via Na2SeO3/Vc redox reaction, followed by coating with red blood cell membrane (RBC) to form core-shell structure polysaccharide-selenium nanoparticles (RBC@BBP-24-3Se). The particle size of BBP-24-3Se (167.1 nm) was increased to 239.8 nm (RBC@BBP-24-3Se) with an obvious core-shell structure after coating with RBC. FT-IR and XPS results indicated that the interaction between BBP-24-3 and SeNPs formed a new C-O···Se bond with valence state of Se0. Bioassays indicated that RBC coating markedly enhanced both the biocompatibility and bioabsorbability of RBC@BBP-24-3Se, and the absorption rate of RBC@BBP-24-3Se in HepG2 cells was 4.99 times higher than that of BBP-24-3Se at a concentration of 10 µg/mL. Compared with BBP-24-3Se, RBC@BBP-24-3Se possessed significantly heightened protective efficacy against oxidative damage and better regulation of glucose/lipid metabolism disorder induced by palmitic acid in HepG2 cells. Mechanistic studies demonstrated that RBC@BBP-24-3Se could effectively improve PI3K/AKT signaling pathway to promote glucose metabolism, inhibit the expression of lipid synthesis genes and up-regulate the expression of lipid-decomposing genes through AMPK signaling pathway to improve lipid metabolism. These results provided a theoretical basis for developing a new type of selenium supplement for the treatment of insulin resistance.
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Glucosa , Metabolismo de los Lípidos , Nanopartículas , Polisacáridos , Rubus , Selenio , Humanos , Selenio/química , Células Hep G2 , Polisacáridos/farmacología , Polisacáridos/química , Metabolismo de los Lípidos/efectos de los fármacos , Glucosa/metabolismo , Nanopartículas/química , Rubus/química , Tamaño de la Partícula , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Primary cardiac angiosarcoma is a rare malignant soft-tissue sarcoma derived from vascular endothelial cells or lymphatic endothelial cells, with a high malignancy, poor prognosis, and a lack of effective medical therapy. This article reports on two patients with primary cardiac angiosarcoma who received first-line treatment with multi-targeted anti-angiogenic agent, anlotinib monotherapy. The treatment rapidly controlled pleural and pericardial effusion, significantly reduced the tumor, improved symptoms, and showed satisfactory recent efficacy. This indicates that anlotinib offers a new first-line treatment option for advanced primary cardiac angiosarcoma.
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Background: Tetrahydrobiopterin (BH4) deficiency is a rare cause of hyperphenylalaninemia (HPA). The incidence of this condition varies based on region and ethnicity. In the early stages, patients typically do not exhibit any symptoms, and HPA is identified only through newborn screening for diseases. It is important to distinguish BH4 deficiency from phenylketonuria (PKU, MIM # 261600). Timely diagnosis and treatment of BH4 deficiency are crucial for the prognosis of patients. Case presentation: We present two rare cases of Chinese Tibetan children with BH4D, diagnosed through biochemical tests and genetic sequencing. Case 1 is a male infant, 2 months old, with a newborn screening (NBS) Phe level of 1212 µmol/L (reference range <120 µmol). The biopterin(B) level was 0.19 mmol/molCr (reference range: 0.42-1.92 mmol/molCr), with a B% of 5.67% (reference range: 19.8%-50.3%). Gene sequencing revealed a homozygous missense variant [NM_000317.3 (PTS): c.259C > T (p.Pro87Ser), rs104894276, ClinVar variation ID: 480]. The patient was treated with a Phe-reduced diet and oral sapropterin, madopar and is currently 3 years and 4 months old, showing mild global developmental delay. Case 2 is a 40-day-old female infant with a Phe level of 2442.11 µmol/L and dihydropteridine reductase (DHPR) activity of 0.84 nmol/(min. 5 mm disc) (reference range: 1.02-3.35 nmol/min.5 mm disc. Gene sequencing revealed a compound heterozygous genotype [NM_000320.3(QDPR): c.68G > A (p.Gly23Asp), rs104893863, ClinVar Variation ID: 490] and [NM_000320.3(QDPR) c.419C > A (p. Ala140Asp), ClinVar ID: 2444501]. The patient was treated with a Phe-reduced diet and oral madopar, 5-hydroxytryptophan. At the age of 1 year, she exhibited severe global developmental delay with seizures. Conclusion: We identified and treated two cases of BH4D in Tibetan populations in China, marking the first confirmed instances. Our report emphasizes the significance of conducting differential diagnosis tests for BH4D.
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The tooth serves as an exemplary model for developmental studies, encompassing epithelial-mesenchymal transition and cell differentiation. The essential factors and pathways identified in tooth development will help understand the natural development process and the malformations of mineralized tissues such as skeleton. The time-dependent proteomic changes were investigated through the proteomics of healthy human molars during embryonic stages, ranging from the cap-to-early bell stage. A comprehensive analysis revealed 713 differentially expressed proteins (DEPs) exhibiting five distinct temporal expression patterns. Through the application of weighted gene co-expression network analysis (WGCNA), 24 potential driver proteins of tooth development were screened, including CHID1, RAP1GDS1, HAPLN3, AKAP12, WLS, GSS, DDAH1, CLSTN1, AFM, RBP1, AGO1, SET, HMGB2, HMGB1, ANP32A, SPON1, FREM1, C8B, PRPS2, FCHO2, PPP1R12A, GPALPP1, U2AF2, and RCC2. Then, the proteomics and transcriptomics expression patterns of these proteins were further compared, complemented by single-cell RNA-sequencing (scRNA-seq). In summary, this study not only offers a wealth of information regarding the molecular intricacies of human embryonic epithelial and mesenchymal cell differentiation but also serves as an invaluable resource for future mechanistic inquiries into tooth development.
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BACKGROUND/AIM: Tuberous sclerosis complex (TSC) is a multi-system syndrome caused by loss-of-function mutation in TSC1 or TSC2. Most TSC patients present with cardiac rhabdomyoma or cortical tubers during fetal life, and the symptoms are not uniform as their age. The gene products of TSC1/2 are components of the TSC protein complex and are important role in the PI3K/AKT/mTOR (PAM) signaling pathway. Based on three members of a family with variable expressivity, the purpose of this study was to clarify the clinical features of TSC in different age groups and to analyze the genetic characteristics of TSC2 gene. METHODS: Clinical exome sequencing and co-segregation were used to identify a three-generation family with four affected individuals. HEK-293T cell model was constructed for subsequent experiments. Quantitative RT-PCR, western blotting, and subcellular localization were used to analyze the expression effect of TSC2 mutation. CCK-8 assay, wound healing assay, and cell cycle analysis were used to analyze the function effect of TSC2 mutation. RESULT: We identified a TSC family with heterozygous deletion of exon 4 in TSC2 by clinical exon sequencing. Sanger sequencing indicated that the affected individuals have 2541-bp deletion that encompassed exon 4 and adjacent introns. Deletion of exon 4 decreased the TSC2 mRNA and protein levels in HEK-293T cells, and activated the PI3K/AKT/mTOR pathway, thereby altering the cell cycle and promoting cell proliferation and migration. CONCLUSION: We confirmed the pathogenicity of the large deletion in TSC2 in a three- generations family.. Deletion of exon 4 of TSC2 affected cell proliferation, migration, and cell cycle via abnormal activation of the PAM pathway. This study evaluated the pathogenic effect of deletion of exon 4 of TSC2 and investigated the underlying mechanism.
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Esclerosis Tuberosa , Proteínas Supresoras de Tumor , Humanos , Mutación , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/genética , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/patología , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Introduction: We report a fatal case of massive airway bleeding caused by pulmonary strongyloidiasis in a patient with a transplanted kidney. Case Presentation: A 47-year-old male, regularly taking immunosuppressants post-kidney transplant, visited our hospital with symptoms of abdominal bloating, nausea, and emesis persisting for three days. After hospitalization, he developed a cough, hemoptysis, and respiratory failure. Sputum analysis confirmed an infestation with Strongyloides stercoralis. Despite receiving albendazole therapy and bronchoscopic management for bronchial hemorrhage, the patient ultimately died due to acute respiratory and circulatory collapse triggered by severe airway bleeding. Conclusion: Patients undergoing immunosuppressive therapy following kidney transplantation are at increased risk for disseminated strongyloidiasis. Consequently, infectious disease screening prior to transplantation, along with essential preventive pharmacotherapy, is of paramount importance.
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Background: This study aims to evaluate the immunological features of gastrointestinal (GI) bleeding in children with Henoch-Schönlein purpura (HSP). Study Design: This retrospective study was conducted on children with HSP. Demographic and clinical data were collected, including serum immunoglobulin (Ig) levels, complement C3 and C4 levels, and lymphocyte subtype percentage. Results: A total of 446 hospitalized children had HSP. Eighty-six children with HSP had GI bleeding, 114 had proteinuria, and 107 had hematuria. Lower arthralgia, prolonged glucocorticoid use, increased white blood cell counts, elevated neutrophils and neutrophil-to-lymphocyte ratio, reduced IgG and C3 levels, elevated CD19+ cell percentage, and reduced CD3+ cell and natural killer cell percentages were associated with GI bleeding risk in patients with HSP. Multivariate regression analysis revealed that arthralgia, glucocorticoid use, increased neutrophil percentage, reduced IgG and C3 levels, and increased CD19+ cell percentage were independent predictors of GI bleeding. Further analysis indicated that the combination of C3 and CD19+ cell percentages had a high predictive ability for GI bleeding in children with HSP. Conclusion: This study indicated that reduced C3 and increased CD19+ cell percentages contributed to the development of GI bleeding in children with HSP. Specific immunologic profiles may be strongly correlated with GI bleeding risk in children with HSP.
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Background: The modulating effects of probiotics and fecal microbiota transplantation (FMT) on gut flora and their direct antitumor effects remain unclear in dirty rats with established primary liver cancer. Materials & methods: Probiotics (VSL#3), FMT or tap water were administrated to three groups. Fresh fecal samples were collected from all groups for 16S rRNA analysis. Liver cancer tissues were collected to evaluate the tumor response. Results: Significant modulation of ß-diversity (p = 0.023) was observed after FMT. VSL#3 and FMT had no inhibitory effect on tumors, but the density of Treg cells decreased (p = 0.031) in the FMT group. Conclusion: FMT is a more attractive alternative to probiotics in dirty rats with liver cancer.
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Neoplasias Hepáticas , Probióticos , Ratas , Animales , Trasplante de Microbiota Fecal , ARN Ribosómico 16S/genética , Heces , Probióticos/farmacología , Neoplasias Hepáticas/terapiaRESUMEN
Gardner syndrome (GS) is a specific form of familial adenomatous polyposis (FAP), which manifests as colorectal polyps, multiple osteomas and soft tissue tumors, and in the oral cavity as osteomas of the jaws, odontomas, and abnormal tooth counts. The underlying cause of GS is attributed to mutations in the APC gene. Mutations in this gene disrupt the normal functioning of the protein and lead to the development of GS. To further investigate GS, a family affected by the syndrome was selected from Dongguan, Guangdong Province. The family members underwent a comprehensive survey, which involved collecting clinical data and peripheral venous blood samples. The samples were then used for genetic analysis. Whole exome sequencing (WES) and Sanger sequencing techniques were utilized to screen and identify specific mutation sites in the APC gene. The clinical findings for the GS family included the presence of gastrointestinal polyps and odontomas. After analyzing the genetic sequencing results, a novel mutation site c.4266dupA on the APC gene was found in the patients, which leading to the APC protein truncation. As a result of this study, it is suggested that odontoma may be an early indicator of GS. Additionally, the identification of this novel mutation site in the APC gene expands the known spectrum of genetic mutations associated with the disease. This discovery has significant implications for the early diagnosis of GS, thus enabling timely intervention to reduce the risk of developing colon cancer and other related diseases.