The prognostic and immunological role of MCM3 in pan-cancer and validation of prognosis in a clinical lower-grade glioma cohort.

Background: Previous studies have shown that MCM3 plays a key role in initiating DNA replication. However, the mechanism of MCM3 function in most cancers is still unknown. The aim of our study was to explore the expression, prognostic role, and immunological characteristics of MCM3 across cancers. Methods: We explored the expression pattern of MCM3 across cancers. We subsequently explored the prognostic value of MCM3 expression by using univariate Cox regression analysis. Spearman correlation analysis was performed to determine the correlations between MCM3 and immune-related characteristics, mismatching repair (MMR) signatures, RNA modulator genes, cancer stemness, programmed cell death (PCD) gene expression, tumour mutation burden (TMB), microsatellite instability (MSI), and neoantigen levels. The role of MCM3 in predicting the response to immune checkpoint blockade (ICB) therapy was further evaluated in four immunotherapy cohorts. Single-cell data from CancerSEA were analysed to assess the biological functions associated with MCM3 in 14 cancers. The clinical correlation and independent prognostic significance of MCM3 were further analysed in the TCGA and CGGA lower-grade glioma (LGG) cohorts, and a prognostic nomogram was constructed. Immunohistochemistry in a clinical cohort was utilized to validate the prognostic utility of MCM3 expression in LGG. Results: MCM3 expression was upregulated in most tumours and strongly associated with patient outcomes in many cancers. Correlation analyses demonstrated that MCM3 expression was closely linked to immune cell infiltration, immune checkpoints, MMR genes, RNA modulator genes, cancer stemness, PCD genes and the TMB in most tumours. There was an obvious difference in outcomes between patients with high MCM3 expression and those with low MCM3 expression in the 4 ICB treatment cohorts. Single-cell analysis indicated that MCM3 was mainly linked to the cell cycle, DNA damage and DNA repair. The expression of MCM3 was associated with the clinical features of LGG patients and was an independent prognostic indicator. Finally, the prognostic significance of MCM3 in LGG was validated in a clinical cohort. Conclusion: Our study suggested that MCM3 can be used as a potential prognostic marker for cancers and may be associated with tumour immunity. In addition, MCM3 is a promising predictor of immunotherapy responses.

Phase 2 study of pegylated liposomal doxorubicin plus cyclophosphamide, vincristine/vindesine, and prednisone in newly diagnosed PTCL: 8-year results.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. This phase 2 study evaluated the efficacy and safety of the PLD-containing CHOP regimen in newly diagnosed patients with aggressive peripheral T-cell lymphomas (PTCL). METHODS: Patients received PLD, cyclophosphamide, vincristine/vindesine, plus prednisone every 3 weeks for up to 6 cycles. The primary endpoint was the objective response rate at the end of treatment (EOT). RESULTS: From September 2015 to January 2017, 40 patients were treated. At the EOT, objective response was achieved by 82.5% of patients, with 62.5% complete response. As of the cutoff date (September 26, 2023), median progression-free survival (mPFS) and overall survival (mOS) were not reached (NR). The 2-year, 5-year, and 8-year PFS rates were 55.1%, 52.0%, and 52.0%. OS rate was 80.0% at 2 years, 62.5% at 5 years, and 54.3% at 8 years. Patients with progression of disease within 24 months (POD24) had worse prognosis than those without POD24, regarding mOS (41.2 months vs NR), 5-year OS (33.3% vs 94.4%), and 8-year OS (13.3% vs 94.4%). Common grade 3-4 adverse events were neutropenia (87.5%), leukopenia (80.0%), anemia (17.5%), and pneumonitis (17.5%). CONCLUSION: This combination had long-term benefits and manageable tolerability, particularly with less cardiotoxicity, for aggressive PTCL, which might provide a favorable benefit-risk balance. CLINICALTRIALS.GOV IDENTIFIER: Chinese Clinical Trial Registry, ChiCTR2100054588; IRB Approved: Ethics committee of Fudan University Shanghai Cancer Center (Date 2015.8.31/No. 1508151-13.

Honokiol Suppresses Cell Proliferation and Tumor Migration through ROS in Human Anaplastic Thyroid Cancer Cells.

BACKGROUND: Honokiol is a natural polyphenolic compound extracted from Magnolia officinali, which is commonly used material in Chinese herbal medicine, has a variety of biological functions, including anti-tumor, anti-oxidant, anti-inflammation, anti-microbial and anti-allergy. Although honokiol has numerous beneficial effects on human diseases, the underlying mechanisms of tumor metastasis are still unclear. Previously, we reported that honokiol suppresses thyroid cancer cell proliferation with cytotoxicity through cell cycle arrest, apoptosis, and dysregulation of intracellular hemostasis. Herein, we hypothesized that the antioxidant effect of honokiol might play a critical role in thyroid cancer cell proliferation and migration. METHODS: The cell viability assays, cellular reactive oxygen species (ROS) activity, cell migration, and immunoblotting were performed after cells were treated with honokiol. RESULTS: Based on this hypothesis, we first demonstrated that honokiol suppresses cell proliferation in two human anaplastic thyroid carcinoma (ATC) cell lines, KMH-2 and ASH-3, within a dosage- and time-dependent manner by cell counting kit-8 (CCK-8) assay. Next, we examined that honokiol induced ROS activation and could be suppressed by pre-treated with an antioxidant agent, N-acetyl-l-cysteine (NAC). Furthermore, the honokiol suppressed cell proliferation can be rescued by pre-treated with NAC. Finally, we demonstrated that honokiol inhibited ATC cell migration by modulating epithelial-mesenchymal transition (EMT)-related markers by Western blotting. CONCLUSION: Taken together, we provided the potential mechanism for treating ATC cells with honokiol, which significantly suppresses tumor proliferation and inhibits tumor metastasis in vitro through reactive oxygen species (ROS) induction.

Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function.

Individuals with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of aging related health conditions and all-cause mortality, but whether CHIP affects risk of infection is much less clear. Using UK Biobank data, we revealed a positive association between CHIP and incident pneumonia in 438,421 individuals. We show that inflammation enhanced pneumonia risk, as CHIP carriers with a hypomorphic IL6 receptor polymorphism were protected. To better characterize the pathways of susceptibility, we challenged hematopoietic Tet Methylcytosine Dioxygenase 2-knockout (Tet2-/-) and floxed control mice (Tet2fl/fl) with Streptococcus pneumoniae. As with human CHIP carriers, Tet2-/- mice had hematopoietic abnormalities resulting in the expansion of inflammatory monocytes and neutrophils in peripheral blood. Yet, these cells were insufficient in defending against S. pneumoniae and resulted in increased pathology, impaired bacterial clearance, and higher mortality in Tet2-/- mice. We delineated the transcriptional landscape of Tet2-/- neutrophils and found that, while inflammation-related pathways were upregulated in Tet2-/- neutrophils, migration and motility pathways were compromised. Using live-imaging techniques, we demonstrated impairments in motility, pathogen uptake, and neutrophil extracellular trap (NET) formation by Tet2-/- neutrophils. Collectively, we show that CHIP is a risk factor for bacterial pneumonia related to innate immune impairments.

K33 only mutant ubiquitin augments bone marrow-derived dendritic cell-mediated CTL priming via PI3K-Akt pathway.

To explore the effect of K33 only mutant ubiquitin (K33O) on bone marrow-derived dendritic cells' (BMDCs') maturity, antigen uptake capability, surface molecule expressions and BMDC-mediated CTL priming, and further investigate the role of PI3K-Akt engaged in K33O-increased BMDC maturation, antigen uptake and presentation, surface molecule expressions and BMDC-based CTL priming. BMDCs were conferred K33O and other ubiquitin mutants (K33R, K48R, K63R-mutant ubiquitin) incubation or LY294002 and wortmannin pretreatment. PI3K-Akt phosphorylation, antigen uptake, antigenic presentation and CD86/MHC class I expression in BMDC were determined by western blot or flow cytometry. BMDC-based CTL proliferation and priming were determined by in vitro mixed lymphocyte reaction (MLR), ex vivo enzyme-linked immunospot assay (Elispot) and flow cytometry with intracellular staining, respectively. The treatment with K33O effectively augmented PI3K-Akt phosphorylation, BMDCs' antigen uptake, antigenic presentation, CD86/MHC class I and CD11c expressions. MLR, Elispot and flow cytometry revealed that K33O treatment obviously enhanced CTL proliferation, CTL priming and perforin/granzyme B expression. The pretreatment with PI3K-Akt inhibitors efficiently abrogated K33O's effects on BMDC. The replenishment of K33 only mutant ubiquitin augments BMDC-mediated CTL priming in bone marrow-derived dendritic cells via PI3K-Akt signalling.

A latent profile analysis of resilience and their relation to differences in sleep quality in patients with lung cancer.

PURPOSE: Sleep problems are a significant issue in patients with lung cancer, and resilience is a closely related factor. However, few studies have identified subgroups of resilience and their relationship with sleep quality. This study aimed to investigate whether there are different profiles of resilience in patients with lung cancer, to determine the sociodemographic characteristics of each subgroup, and to determine the relationship between resilience and sleep quality in different subgroups. METHODS: A total of 303 patients with lung cancer from four tertiary hospitals in China completed the General Sociodemographic sheet, the Connor-Davidson Resilience Scale, and the Pittsburgh Sleep Quality Index. Latent profile analysis was applied to explore the latent profiles of resilience. Multivariate logistic regression was used to analyze the sociodemographic variables in each profile, and ANOVA was used to explore the relationships between resilience profiles and sleep quality. RESULTS: The following three latent profiles were identified: the "high-resilience group" (30.2%), the "moderate-resilience group" (46.0%), and the "low-resilience group" (23.8%). Gender, place of residence, and average monthly household income significantly influenced the distribution of resilience in patients with lung cancer. CONCLUSION: The resilience patterns of patients with lung cancer varied. It is suggested that health care providers screen out various types of patients with multiple levels of resilience and pay more attention to female, rural, and poor patients. Additionally, individual differences in resilience may provide an actionable means for addressing sleep problems.

Clinical value of ultrasound in adult Wilms' tumor patient with uremia: A case report and literature review.

RATIONALE: Wilms' tumor (WT) is the most common pediatric kidney malignancy and is rarely found in adults. Nonspecific clinical symptoms and imaging features often lead to delayed diagnosis or misdiagnosis of adult WT, resulting in poor clinical outcomes. Ultrasound (US), as an efficient and noninvasive examination method, has been widely used in clinical diagnosis and treatment. Therefore, various US evidence is meaningful to improve understanding of adult WT characteristics in ultrasound. PATIENT CONCERNS: A 45-year-old female patient with uremia (regular hemodialysis for 13 years) with painless gross hematuria was diagnosed with a right kidney tumor penetrating to the lung. Preoperatively, B-mode ultrasonography showed an ill-defined hyperechoic mass in the right kidney, which revealed an unclear border, uneven internal echoes, and calcification. Besides, the internal blood flow signal of the tumor was detected. Contrast-enhanced ultrasound (CEUS) showed an uneven hyper-enhancement in the tumor ("fast in and slow out"). Contrast-enhanced computed tomography of the kidney indicated a similar result as the CEUS. Moreover, the chest CT identified multiple pulmonary metastatic nodules. DIAGNOSES: An ultrasound-guided percutaneous core needle biopsy of the tumor proceeded to make a definite diagnosis of adult WT (epithelial type). INTERVENTIONS: The patient was treated with tislelizumab. OUTCOMES: No progress was found to date. LESSONS: We report the first case in which CEUS was performed in an adult WT patient with uremia and multiple pulmonary metastases. The features obtained by the US can help in the diagnosis of adult WT and direct further diagnostic procedures.

Distinct roles of core autophagy-related genes in zebrafish definitive hematopoiesis.

Despite the well-described discrepancy between ATG (macroautophagy/autophagy-related) genes in the regulation of hematopoiesis, varying essentiality of core ATG proteins in vertebrate definitive hematopoiesis remains largely unclear. Here, we employed zebrafish (Danio rerio) to compare the functions of six core atg genes, including atg13, becn1 (beclin1), atg9a, atg2a, atg5, and atg3, in vertebrate definitive hematopoiesis via clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 ribonucleoprotein and morpholino targeting. Zebrafish with various atg mutations showed autophagic deficiency and presented partially consistent hematopoietic abnormalities during early development. All six atg mutations led to a declined number of spi1b+ (Spi-1 proto-oncogene b) myeloid progenitor cells. However, only becn1 mutation resulted in the expansion of myb+ (v-myb avian myeloblastosis viral oncogene homolog) hematopoietic stem and progenitor cells (HSPCs) and transiently increased coro1a+ (coronin, actin binding protein, 1A) leukocytes, whereas atg3 mutation decreased the number of HSPCs and leukocytes. Proteomic analysis of caudal hematopoietic tissue identified sin3aa (SIN3 transcription regulator family member Aa) as a potential modulator of atg13- and becn1-regulated definitive hematopoiesis. Disruption of sin3aa rescued the expansion of HSPCs and leukocytes in becn1 mutants and exacerbated the decrease of HSPCs in atg13 mutants. Double mutations were also performed to examine alternative functions of various atg genes in definitive hematopoiesis. Notably, becn1 mutation failed to induce HSPCs expansion with one of the other five atg mutations. These findings demonstrated the distinct roles of atg genes and their interplays in zebrafish definitive hematopoiesis, thereby suggesting that the vertebrate definitive hematopoiesis is regulated in an atg gene-dependent manner.Abbreviations: AGM: aorta-gonad-mesonephros; AO: acridine orange; atg: autophagy related; becn1: beclin 1, autophagy related; CHT: caudal hematopoietic tissue; CKO: conditional knockout; coro1a: coronin, actin binding protein, 1A; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; dpf: days post fertilization; FACS: fluorescence-activated cell sorting; hbae1.1: hemoglobin, alpha embryonic 1.1; HSCs: hematopoietic stem cells; HSPCs: hematopoietic stem and progenitor cells; KD: knockdown; KO: knockout; map1lc3/lc3: microtubule-associated protein 1 light chain 3; MO: morpholino; mpeg1.1: macrophage expressed 1, tandem duplicate 1; mpx: myeloid-specific peroxidase; myb: v-myb avian myeloblastosis viral oncogene homolog; PE: phosphatidylethanolamine; p-H3: phospho-H3 histone; PtdIns3K: class 3 phosphatidylinositol 3-kinase; rag1: recombination activating 1; rb1cc1/fip200: RB1-inducible coiled-coil 1; RFLP: restriction fragment length polymorphism; RNP: ribonucleoprotein; sin3aa: SIN3 transcription regulator family member Aa; spi1b: Spi-1 proto-oncogene b; ulk: unc-51 like autophagy activating kinase; vtg1: vitellogenin 1; WISH: whole-mount in situ hybridization.

Cinnamyl Chalcone Based AIE Fluorescent Probes for Sensitive Detection of Hydrazine and its Application in Living Cells.

Widely utilized in the chemical industry and agriculture, hydrazine is easily absorbed by living things and can cause physical harm when in touch for an extended period of time. As a result, a novel cinnamaldehyde chalcone C5 was produced by Friedel Crafts process and aldol condensation reaction. Triphenylamine was used as the raw material for hydrazine determination in both reactions. Chalcone C5 exhibits significant AIE behavior in a mixed mixture of ethanol and water in addition to having great selectivity and a low detection limit (0.119 nm) for hydrazine. The solvent effect test revealed a linear relationship between the Stokes shift of C5 in the solvent and the rise in solvent orientation polarization. It is important to note that C5 is not harmful to MCF-7 cells, mouse kidney cells, or pig kidney cells. Furthermore, research on cell imaging has demonstrated that probe C5 may be utilized to image the fluorescence of hydrazine in active MCF-7 cells.

Piperlongumine Induces Cellular Apoptosis and Autophagy via the ROS/Akt Signaling Pathway in Human Follicular Thyroid Cancer Cells.

Thyroid cancer (TC) is the most common endocrine malignancy. Recently, the global incidence of TC has increased rapidly. Differentiated thyroid cancer includes papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), which are the most common types of TC. Although PTCs and FTCs exert good prognoses and high survival rates, FTCs tend to be more aggressive than PTCs. There is an urgent need to improve patient outcomes by developing effective therapeutic agents for FTCs. Piperlongumine exerts anti-cancer effects in various human carcinomas, including human anaplastic TCs and PTCs. However, the anti-cancer effects of piperlongumine in FTCs and the underlying mechanisms are yet to be elucidated. Therefore, in the present study, we evaluated the effect of piperlongumine on cell proliferation, cell cycle, apoptosis, and autophagy in FTC cells with flowcytometry and Western blot. We observed that piperlongumine caused growth inhibition, cell cycle arrest, apoptosis induction, and autophagy elevation in FTC cells. Activities of reactive oxygen species and the downstream PI3K/Akt pathway were the underlying mechanisms involved in piperlongumine mediated anti-FTC effects. Advancements in our understanding of the effects of piperlongumine in FTC hold promise for the development of novel therapeutic strategies.

The diagnostic value of circulating abnormal cells in early lung cancer.

Lung cancer is the leading cause of cancer-related deaths globally. Early detection of lung cancer can lead to more effective treatment and improved survival. Circulatory abnormal cells (CACs) with specific chromosomal variation may be used to diagnose lung cancer and to differentiate benign from malignant nodules. The value of CAC in precancer diagnosis, however, remains controversial. In this study, a systematic review and meta-analysis are conducted to clarify the diagnostic value of CAC in early-stage lung cancer. A systematic literature search was conducted using the following medical topic title terms and text-free words: "circulating genetically abnormal cells", "CACs", "liquid biopsy", "early lung cancer", "non-small cell lung cancer", "diagnostic accuracy", "sensitivity" and "specificity" in Science Direct, CNKI and Wanfang databases, respectively. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and area under the curve were analyzed by STATA15.0 (MP) software. Deek funnel plots were used to assess potential publication bias. Heterogeneity was tested using the I2 statistic and the Cochrane Q test. 7 major studies were included in this meta-analysis, and a total of 53728 participants were analyzed. In the diagnosis of early lung cancer, CAC had pooled sensitivity, specificity, and receiver operating characteristics of 0.80 (95% CI: 0.73-0.86), 0.85 (95% CI: 0.69-0.94), and 0.87 (95% CI: 0.84-0.90). The combined positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and diagnostic score were 23.36 (95% CI: 7.33-74.46), 5.42 (95% CI: 2.37-12.43), 0.23 (95% CI: 0.16-0.35) and 3.15 (95% CI: 1.99-4.31) respectively. Publication bias was not detected. The CAC is effective at detecting lung cancer in its early stages.

Prospective study on the clinical and economic burden of venous leg ulcers in the tropics.

OBJECTIVE: Venous leg ulcers (VLUs) are both chronic and recurrent. The treatment of such ulcers often require multiple outpatient visits and dressing changes. Several reports on the costs of treating such VLUs have been reported in the west. We prospectively evaluated the clinical and economic burden of VLUs in a population of Asian patients in the tropics. METHODS: Patients from a prospective two-center study conducted at two tertiary hospitals in Singapore, as a part of the Wound Care Innovation in the Tropics program, between August 2018 and September 2021 were recruited. The patients were followed up for 12 weeks (visit 1 to visit 12), until index ulcer healing, death, or lost to follow-up (whichever came first). These patients were then followed up 12 weeks later to determine the longer term outcome of the wound (healed, recurrence, remained unhealed). The itemized costs derived from the medical service were retrieved from the relevant departments of the study sites. The patients' health-related quality of life was assessed at baseline and the last visit of the 12-week follow-up period (or until index ulcer healing), using the official Singapore version of the EuroQol five-dimension-5L questionnaire, which also includes a visual analog scale (EQ-VAS). RESULTS: A total of 116 patients were enrolled; 63% were men, and the mean patient age was 64.7 years. Of the 116 patients, 85 (73%) had a healed ulcer at 24 weeks (mean duration to ulcer healing, 49 days), and 11 (12.9%) had experienced ulcer recurrence within the study period. Within the 6-month follow-up period, the mean direct healthcare cost per patient was USD$1998. The patients with healed ulcers had significantly lower costs per patient compared with those with unhealed ulcers (USD$1713 vs USD$2780). Regarding health-related quality of life, 71% of the patients had a lower quality of life at baseline, which had improved at 12 weeks of follow-up, with only 58% of the patients reported to have a lower quality of life. Also, the patients with healed ulcers scored higher for both utilities (societal preference weights) and EQ-VAS at follow-up (P < .001). In contrast, patients with unhealed ulcers only scored higher EQ-VAS at follow-up (P = .003). CONCLUSIONS: The findings from this exploratory study provide information on the clinical, quality of life, and economic burden of VLUs in an Asian population and suggest the importance of healing VLUs to reduce the effects on patients. The present study provides data as a basis for economic evaluation as a consideration for the treatment of VLUs.

18ß-glycyrrhetinic Acid Modulated Autophagy is Cytotoxic to Breast Cancer Cells.

The development of endocrine therapy resistance in the luminal A subtype of breast cancer is related to the appearance of protective autophagy. The bioactive component from the root of licorice, 18ß-glycyrrhetinic acid (18ß-GA), has many antitumor properties. Whether 18ß-GA can modulate autophagy to inhibit proliferation of the luminal A subtype is still unclear. The proportion of apoptosis caused by 18ß-GA in MCF-7 and T-47D cells was determined using flow cytometry. The autophagy marker, LC3-II conversion, was investigated using Western blotting, and a PremoTM Tandem Autophagy Sensor Kit. We found that the concentration (150-µM) of 18ß-GA caused caspase-dependent apoptosis and LC3-II accumulation or blocked autophagic flux. Moreover, 18ß-GA-mediated apoptosis was improved using rapamycin but reversed by 3-methyladenine (3-MA) addition. The phosphorylation level of Jun-amino-terminal kinase (JNK) was increased significantly in the 18ß-GA treatment and combined incubation using rapamycin. A JNK inhibitor (SP600125) significantly inhibited 18ß-GA-mediated apoptosis, LC3-II accumulation and rescued the numbers of MCF-7 and T-47D colony formation. Especially, 18ß-GA can inhibit xenograft tumor growth in BALB/c nude mice. These data indicate the combination of 18ß-GA with rapamycin or 3-MA can sensitize or decrease MCF-7 and T-47D cells to 18ß-GA-induced apoptosis, respectively. 18ß-GA modulated autophagy is cytotoxic to luminal A subtype breast cancer cells through apoptosis promotion and JNK activation.

Extract of Bletilla formosana callus elevates cellular antioxidative activity via Nrf2/HO-1 signaling pathway and inhibits melanogenesis in zebrafish.

BACKGROUND: Bletilla species are endangered terrestrial orchids used in natural skin care formulas in Asia for a long history. In order to explore the bioactivity potential of Bletilla species as a cosmetic ingredient in a sustainable resource manner, the callus of Bletilla formosana (Hayata) Schltr. was established and extracted by an eco-friendly supercritical fluid CO2 extraction (SFE-CO2) method. The intracellular reactive oxygen species (ROS) scavenging activity and antioxidation-related gene expression of the callus extract were evaluated in both Hs68 fibroblast cells and HaCaT keratinocytes. The melanogenesis-inhibitory effect was investigated in B16F10 melanoma cells and in an in vivo zebrafish model. RESULTS: The calli of B. formosana were propagated for 10-15 generations with a consistent yellow friable appearance and then subjected to SFE-CO2 extraction to obtain a yellow pasty extract. Obvious intracellular ROS scavenging activity of the extract was detected in both Hs68 and HaCaT cells with 64.30 ± 8.27% and 32.50 ± 4.05% reduction at the concentration of 250 µg/mL. Moreover, marked expression levels of heme oxygenase-1 (HO-1) and (NAD(P)H) quinone oxidoreductase-1 (NQO1) genes were detected after 6-h and 24-h treatments. These results indicate the cellular antioxidative activity of B. formosana callus extract was probably activated via the nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 signaling pathway. Melanogenesis-inhibitory effect of the extract was observed in α-MSH stimuli-inducing B16F10 cells with 28.46% inhibition of intracellular melanin content at the concentration of 50 µg/ml. The effect was confirmed with in vivo zebrafish embryos that showed a relative pigmentation density of 80.27 ± 7.98% at the concentration of 100 µg/mL without toxicity. CONCLUSION: Our results shed light on a sustainable utilization of Bletilla species as a potential ingredient for skin.

Synchronous Hepatoblastoma and Neuroblastoma in Two Chinese Infants.

Background: Commonly, pediatric solid tumors occur independently. Only two patients with synchronous hepatoblastoma (HBL) and neuroblastoma (NBL) have been reported. Case reports: Two Chinese infants presented with abdominal mass at 10 and 8 months. Computed tomography (CT) scans in both revealed hepatic masses with additional mediastinal or adrenal masses. Pathology confirmed synchronous HBLs in the liver and NBLs in the mediastinum and adrenal. Next generation sequencing (NGS) found no remarkable germline mutations. Both patients received gross total resections with chemotherapy before or after surgery. They were followed up for 36 and 8 months, and recovered well. Conclusion: These two cases of synchronous HBL and NBL tumors lacked significant genetic alterations.

Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4.

PURPOSE: Senior-Loken syndrome (SLSN) is an autosomal recessive disorder characterized by retinopathy and nephronophthisis. This study aimed to evaluate whether different phenotypes are associated with different variants or subsets of 10 SLSN-associated genes based on an in-house data set and a literature review. DESIGN: Retrospective case series. METHODS: Patients with biallelic variants in SLSN-associated genes, including NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, SDCCAG8, WDR19, CEP164, and TRAF3IP1, were recruited. Ocular phenotypes and nephrology medical records were collected for comprehensive analysis. RESULTS: Variants in 5 genes were identified in 74 patients from 70 unrelated families, including CEP290 (61.4%), IQCB1 (28.6%), NPHP1 (4.2%), NPHP4 (2.9%), and WDR19 (2.9%). The median age at the onset of retinopathy was approximately 1 month (since birth). Nystagmus was the most common initial sign in patients with CEP290 (28 of 44, 63.6%) or IQCB1 (19 of 22, 86.4%) variants. Cone and rod responses were extinguished in 53 of 55 patients (96.4%). Characteristic fundus changes were observed in CEP290- and IQCB1-associated patients. During follow-up, 70 of the 74 patients were referred to nephrology, among whom nephronophthisis was not detected in 62 patients (88.6%) at a median age of 6 years but presented in 8 patients (11.4%) aged approximately 9 years. CONCLUSIONS: Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy. Therefore, awareness of the genetic and clinical features may facilitate the clinical management of SLSN, especially early intervention of kidney problems for patients with eyes affected first.

Inhibition of endogenous hydrogen sulfide production suppresses the growth of nasopharyngeal carcinoma cells.

Hydrogen sulfide (H2 S) has been widely recognized as one of gasotransmitters. Endogenous H2 S plays a crucial role in the progression of cancer. However, the effect of endogenous H2 S on the development of nasopharyngeal carcinoma (NPC) is still unknown. In this study, aminooxyacetic acid (AOAA, an inhibitor of cystathionine-ß-synthase), dl-propargylglycine (PAG, an inhibitor of cystathionine-γ-lyase), and l-aspartic acid (l-Asp, an inhibitor of 3-mercaptopyruvate sulfurtransferase) were adopted to detect the role of endogenous H2 S in NPC growth. The results indicated that the combine (PAG + AOAA + l-Asp) group had higher inhibitory effect on the growth of NPC cells than the PAG, AOAA, and l-Asp groups. There were similar trends in the levels of apoptosis and reactive oxygen species (ROS). In addition, the combine group exhibited lower levels of phospho (p)-extracellular signal-regulated protein kinase but higher expressions of p-p38 and p-c-Jun N-terminal kinase than those in the AOAA, PAG, and l-Asp groups. Furthermore, the combine group exerted more potent inhibitory effect on NPC xenograft tumor growth without obvious toxicity. In summary, suppression of endogenous H2 S generation could dramatically inhibit NPC growth via the ROS/mitogen-activated protein kinase pathway. Endogenous H2 S may be a novel therapeutic target in human NPC cells. Effective inhibitors for H2 S-producing enzymes could be designed and developed for NPC treatment.

E2F1-Deficient Adipose-Derived Stem Cells Improve Wound Closure in Mice by Up-Regulating Expression of VEGF and TGF-ß1.

BACKGROUND: Wound healing is a widespread health problem that imposes a financial burden on health systems. Cell therapy with genetically modified adipose-derived stem cells (ADSCs) is a promising strategy for dysregulated wound repair. E2F transcription factor 1 (E2F1) is a bidirectional regulator of cytokines. Here, the authors aimed to investigate the impact and potential mechanism of E2F1 -/- ADSCs in promoting the wound healing process. METHODS: Forty-five C57BL/6 mice (specific pathogen-free, male) with 10-mm full-thickness wounds were randomly treated with subcutaneous injection of 2 × 10 6 wild-type ADSCs, 2 × 10 6 E2F1 -/- ADSCs, or phosphate-buffered saline. The wound closure rate was monitored at days 0, 3, 7, 10, and 14 after treatment. The collagen synthesis, angiogenesis, and wound contraction were calculated by Masson, immunohistochemistry, and immunofluorescent staining (CD31 and KI67), Western blotting (α-smooth muscle actin, collagen I, vascular endothelial growth factor, and transforming growth factor-ß1) separately at day 14. In vitro, the conditioned media (CM) of wild-type ADSCs and E2F1 -/- ADSCs were collected to evaluate the impact on proliferation, migration, and angiogenesis. RESULTS: In vivo, the E2F1 -/- ADSC group exhibited increased healing rate, proliferating vessels, and collagen synthesis compared with control at day 14 ( P < 0.05). Moreover, E2F1 -/- ADSCs showed enhanced vascular endothelial growth factor and transforming growth factor-ß1 expression in the wound site and CM, and the CM from E2F1 -/- ADSCs promoted the proliferation, migration, and tube formation of co-cultured cells in vitro ( P < 0.05). CONCLUSION: The E2F1 -/- ADSCs exhibited a strong paracrine ability to improve the vascularization process and collagen deposition, thereby accelerating wound healing in the rodent model. CLINICAL RELEVANCE STATEMENT: These findings show that targeting transcription factor E2F1 could regulate the paracrine function of ADSCs, developing E2F1-modified ADSCs as an effective therapeutic option for wound healing and regeneration.

Neonatal sclerosing cholangitis with novel mutations in DCDC2 (doublecortin domain-containing protein 2) in Chinese children.

Background: Neonatal sclerosing cholangitis (NSC) is a rare and severe autosomal recessive inherited liver disease with mutations in DCDC2, commonly requiring liver transplantation (LT) for decompensated biliary cirrhosis in childhood. Methods: The information of four Chinese patients with NSC caused by mutations in DCDC2 from Children's Hospital of Fudan University were gathered. The four patients' clinicopathological and molecular features were summarized by clinical data, liver biopsy, immunohistochemical, and molecular genetic analysis. Results: All patients presented with jaundice, hepatosplenomegaly, hyperbilirubinemia and bile embolism, and high serum γ-glutamyl transferase activity (GGT). Liver biopsies revealed varying degrees of bile duct hyperplasia, portal-tract inflammation, and/or fibrosis. Whole-exome sequencing (WES) found novel heterozygous variants of c.1024-1G > T /p.? and c.544G > A /p. Gly182Arg in the DCDC2. Conclusion: This study expands the genetic spectrum of DCDC2 in NSC.

Contrast enhanced magnetic resonance imaging-based radiomics nomogram for preoperatively predicting expression status of Ki-67 in meningioma: a two-center study.

Background: The aim of this study was to develop and validate a radiomics nomogram for preoperative prediction of Ki-67 proliferative index (Ki-67 PI) expression in patients with meningioma. Methods: A total of 280 patients from 2 independent hospital centers were enrolled. Patients from center I were randomly divided into a training cohort of 168 patients and a test cohort of 72 patients, and 40 patients from center II served as an external validation cohort. Interoperator reproducibility test, Z-score standardization, analysis of variance (ANOVA), and least absolute shrinkage and selection operator (LASSO) binary logistic regression were used to select radiomics features, which were extracted from contrast-enhanced T1-weighted imaging (CE-T1WI) imaging. The radiomics signature for predicting Ki-67 PI expression was developed and validated using 4 classifiers including logistic regression (LR), decision tree (DT), support vector machine (SVM), and adaptive boost (AdaBoost). Finally, combined radiological characteristics with radiomics signature were used to establish the nomogram to predict the risk of high Ki-67 PI expression in patients with meningioma. Results: Fourteen radiomics features were used to construct the radiomics signature. The radiomics nomogram that incorporated the radiomics signature and radiological characteristics showed excellent discrimination in the training, test, and validation cohorts with areas under the curve of 0.817 (95% CI: 0.753-0.881), 0.822 (95% CI: 0.727-0.916), and 0.845 (95% CI: 0.708-0.982), respectively. In addition, the calibration curve for the nomogram demonstrated good agreement between prediction and actual observation. Conclusions: The proposed contrast enhanced magnetic resonance imaging (MRI)-based radiomics nomogram could be an effective tool to predict the risk of Ki-67 high expression in patients with meningioma.