Chinese Translation and Validation of the Center for Neurologic Study Lability Scale.

INTRODUCTION: Pseudobulbar palsy is a common symptom in patients with amyotrophic lateral sclerosis (ALS), but it is often underdiagnosed or misdiagnosed as other diseases. The Center for Neurologic Study Lability Scale (CNS-LS) is a self-report scale consisting of seven questions designed for evaluating pseudobulbar affect (PBA). The current study aimed to validate a Chinese version of the CNS-LS. METHODS: The Chinese version of the CNS-LS was obtained through a standardized forward-backward translation and cultural adaptation. A total of 105 patients with ALS were recruited from the ALS database of Peking University Third Hospital in Beijing, China, to complete the CNS-LS. The reliability of the Chinese version was determined by the test-retest method, and receiver operating characteristic (ROC) analysis was performed for criterion validity. RESULTS: Of 105 patients with ALS, 37 had symptoms of PBA and were diagnosed with that condition by neurologists. Forty-two patients completed the CNS-LS twice, and there was no statistically significant difference between the scores (Z = -0.896, p = 0.37). The Spearman correlation coefficient between the test and retest scores was 0.940 (p < 0.0005), and the Cronbach alpha coefficient was high (α = 0.905, n = 105). Scores of 12 or higher on the CNS-LS identified PBA with sensitivity of 0.919 and specificity of 0.882. The area under the ROC curve was 0.924. CONCLUSION: The Chinese version of the CNS-LS demonstrated good sensitivity and specificity in the group of patients with ALS enrolled in this study. The CNS-LS should be a useful instrument for clinical and research purposes for patients in this language group.

Utility of Stereotactic Body Radiation Therapy in Establishing Local Control for Patients With Invasive Breast Cancer Not Undergoing Definitive Surgery.

PURPOSE: Surgery is the backbone of breast cancer (BC) treatment. For patients who cannot undergo surgery, improving local control (LC) of the primary tumor is paramount. To that end, this study explored the role of stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Between 2015 and 2022, 21 nonsurgical candidates (10 metastatic, 11 stage IA-IIIC) received 23 SBRT courses to primary BC. Seven were analyzed retrospectively; 15 are currently enrolled in a prospective study. SBRT (40 Gy/5 fractions) was delivered every other day. Follow-up imaging was reviewed. Acute (≤3 months) and late toxicities were evaluated using Common Terminology Criteria for Adverse Events, version 5. LC and overall survival (OS) were estimated using Kaplan-Meier curves. RESULTS: Median age was 78.4 years (45.9-97.3). Median follow-up was 14.7 months (3.3-70.3). Median pre-SBRT index lesion size was 3.1 cm (0.5-14.5) and planning treatment volume was 32.4 cc (11.5-522.4). Initial posttreatment imaging performed at a median 4.0 months (0.6-11.9) post-SBRT demonstrated median decrease in index lesion size of 20.8% (0%-100%); SUV reduction of 65.2% (20.8%-100%). Second follow-up scans at a median 7.8 months post-SBRT showed 62% (0%-100%) and 88% (33.3%-100%) median reduction in tumor size and SUV, respectively, compared with pre-SBRT values. The estimated LC rate was 100% at 6 months and 93.3% at 12, 24, and 36 months. Local progression occurred in 1 case 9.5 months after SBRT, after an initial response. Regional progression occurred in 4 cases (17.4%) at a median 18.6 months (5.2-22.7) post-SBRT. Six patients (35.3%) developed distant progression at a median 2.7 months (0.9-16.2). The estimated OS was 85.7% at 6 months, 69.6% at 12 months, and 63.8% at 24 and 36 months. The rates of acute toxicity were G1: 47.8%, G2: 4.3%, G3: 8.7%, and G4: 0%. CONCLUSIONS: Definitive SBRT for primary BC resulted in good LC in nonsurgical patients and was well-tolerated. Considering the pattern of progression, additional approaches to improve regional/distant control should be investigated.

Preoperative fluorescence in situ hybridization analysis as a predictor of tumor recurrence in patients with non-muscle invasive bladder cancer: a bi-institutional study.

BACKGROUND: Non-muscle invasive bladder cancer (NMIBC) is known for its elevated recurrence rate, necessitating an enhancement in the current risk stratification for recurrence. The urine-based fluorescence in situ hybridization (FISH) assay has emerged as a noninvasive auxiliary tool for detecting bladder cancer. The aim of this study was to explore the potential relationship between the preoperative FISH assay and recurrence, and to develop a FISH-clinical nomogram for predicting the recurrence-free survival (RFS) in NMIBC patients. METHODS: In total, 332 eligible patients were enrolled from two hospitals. The SYSMH cohort was randomly assigned to the training set (n = 168) and the validation set I (n = 72) at a ratio of 7:3, while the SYSUTH cohort was allocated to the validation set II (n = 92). The correlation between the preoperative FISH assay and recurrence was determined through the Cox regression analysis. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used for model construction. The performance of the model was assessed by its discrimination, calibration, and clinical usefulness. RESULTS: We uncovered that chromosome 7 aneuploidy, p16 locus loss, number of the positive FISH sites, and the FISH test result were significantly associated with tumor recurrence. Then, a FISH-clinical nomogram incorporating the FISH test result, T stage, associated CIS, tumor grade, and tumor status was developed. It showed favorable calibration and discrimination with a C-index of 0.683 (95%CI, 0.611-0.756) in the training set, which was confirmed in the validation set I and validation set II with C-indexes of 0.665 (95%CI, 0.565-0.765) and 0.778 (95%CI, 0.665-0.891), respectively. Decision curve analysis revealed the clinical usefulness of the nomogram. Moreover, our proposed nomogram significantly outperformed the guideline-recommended EORTC and CUETO scoring models. CONCLUSION: Our study confirmed the prognostic value of the preoperative FISH assay and proposed a FISH-clinical nomogram to predict RFS in NMIBC patients. Our nomogram can serve as a more precise tool for recurrence risk stratification, which may optimize disease management in bladder cancer and improve patient prognosis.

Clinical efficacy and acceptability of remote fetal heart rate self-monitoring in Southern China.

BACKGROUND: Compared to traditional fetal heart rate monitoring (FHR) for the outpatients in clinic, remote FHR monitoring shows real-time assessment of fetal wellbeing at home. The clinical function of remote FHR monitoring in pregnant wome in outpatient is still unclear. OBJECTIVE: To explore the feasibility of remote FHR self-monitoring in singleton pregnant women from southern China. STUDY DESIGN: This prospective cohort study was conducted at one tertiary center in southern China. Pregnant women used a mobile cardiotocogram device to measure the FHR at least once a week until delivery in the remote group. For the control group, pregnant women underwent traditional FHR monitoring once a week in the outpatient clinic. The rate of cesarean section, risk of postpartum hemorrhage and adverse neonatal outcomes were compared between the two groups. All the pregnant women completed a questionnaire survey to evaluate their acquisition of remote FHR self-monitoring. RESULTS: Approximately 500 women were recruited in the remote FHR self-monitoring group (remote group), and 567 women were recruited in the traditional FHR monitoring group (control group). The women in the remote FHR monitoring group were more likely to be nulliparous (P < 0.001), more likely to have a higher education level (P < 0.001) and more likely to be at high risk (P = 0.003). There was no significant difference in the risk of cesarean section (P = 0.068) or postpartum hemorrhage (P = 0.836) between the two groups. No difference in fetal complications was observed across groups, with the exception of the incidence of NICU stays, which was higher in the remote group (12.0% vs. 8.3%, P = 0.044). The questionnaire survey showed that the interval time (P = 0.001) and cost (P = 0.010) of fetal heart rate monitoring were lower in the remote group. Regarding age, prepregnancy BMI, risk factors, education level, maternal risk and household income, senior high school (OR 2.86, 95% CI 1.67-4.90, P < 0.001), undergraduate (OR 2.96, 95% CI 1.73-5.06, P < 0.001), advanced maternal age (OR 1.42, 95% CI 1.07-1.89, P = 0.015) and high-risk pregnancy (OR 1.61, 95% CI 1.11-2.35, P = 0.013) were independent factors for pregnant women to choose remote fetal monitoring. Multiparty (OR 0.33, 95% CI 0.21-0.51, P < 0.001), full-time motherhood (OR 0.47, 95% CI 0.33-0.678, P < 0.001) and high household income (OR 0.67, 95% CI 0.50-0.88, P = 0.004) were negatively correlated with the choice of remote FHR self-monitoring. CONCLUSION: Remote FHR self-monitoring technology has a lower cost and shows potential clinical efficacy for the outpatient setting in southern China. This approach does not increase the risk of cesarean section or adverse neonatal outcomes. It is acceptable among nulliparous pregnant women with a high education level, high household income or high risk. Further research is needed to assess the impact of this technology on obstetric outcomes in different health settings.

Clinical features and genetic spectrum of Chinese patients with hereditary spastic paraplegia: A 14-year study.

Background: Hereditary spastic paraplegia (HSP) constitutes a group of clinically and genetically rare neurodegenerative diseases characterized by progressive corticospinal tract degeneration. The phenotypes and genotypes of HSP are still expanding. In this study, we aimed to analyse the differential diagnosis, clinical features, and genetic distributions of a Chinese HSP patients in a 14-year cohort and to improve our understanding of the disease. Methods: The clinical data of patients with a primary diagnosis of HSP at the initial visit to the Department of the Neurology, Peking University Third Hospital, from 2008 to 2022 were retrospectively collected. Next-generation sequencing gene panels (NGS) combined with a multiplex ligation-amplification assay (MLPA) were conducted. Epidemiological and clinical features and candidate variants in HSP-related genes were analyzed and summarized. Results: 54 cases (probands from 25 different pedigrees and 29 sporadic cases) from 95 patients with a primary diagnosis of HSP were finally confirmed to have a clinical diagnosis of HSP based on clinical criteria, including their clinical findings, family history and long-term follow-up. Earlier disease onset was associated with longer diagnostic delay and longer disease duration and was associated with a lower risk of loss of ability to walk independently. In addition, 20 candidate variants in reported HSP-related genes were identified in these clinically diagnosed HSP patients, including variants in SPAST, ALT1, WASHC5, SPG11, B4GALNT1, and REEP1. The genetic diagnostic rate in these 54 patients was 35.18%. Conclusion: Hereditary spastic paraplegia has high clinical and genetic heterogeneity and is prone to misdiagnosis. Long-term follow-up and genetic testing can partially assist in diagnosing HSP. Our study summarized the clinical features of Chinese HSP patients in a 14-year cohort, expanded the genotype spectrum, and improved our understanding of the disease.

CMV infection is a risk factor for hemorrhagic cystitis after hematopoietic stem cell transplantation.

Hemorrhagic cystitis (HC) is a common complication after transplantation. The purpose of this study was to examine the incidence and risk factors for HC after hematopoietic stem cell transplantation (HSCT). The records of patients who underwent allogenic HSCT from January 2012 to December 2018 at our institution were retrospectively reviewed. Cox proportional regression and Kaplan-Meier analyses were performed to determine independent risk factors for HC. The statistical analysis was performed in May 2020. A total of 173 patients underwent HSCT, and 53 (30.6%) developed grade 2 or 3 HC cystitis at a median of 37 days (range - 5 to 98 days) after transplantation. Thirty-two patients developed moderate (grade 2) cystitis and 21 severe (grade 3) cystitis. Of the 173 patients, 61 developed acute graft-versus-host disease (GVHD) (median onset day 24) and 79 experienced cytomegalovirus (CMV) reactivation (median onset day 35). The relative risk (RR) of developing a CMV infection for patients with acute GVHD was 2.77 times that of patients without acute GVHD (P < 0.001). CMV infection was the only independent variable significantly associated with HC in both univariate and multivariate analyses. The estimated hazard ratio (HR) of CMV infection for the development of HC was 5.57 (95% confidence interval [CI]: 2.52 to 12.33, P < 0.001). CMV infection is an independent risk factor for the development of HC after HSCT, and acute GVHD is a risk factor for CMV reactivation. Decreasing the frequency of GVHD after HSCT may result in a lower frequency of HC.

Robotic-assisted combined transposition of left renal vein and gonadal vein as a novel treatment option for renal nutcracker syndrome: A case report.

RATIONALE: Renal nutcracker syndrome is a rare phenomenon that often causes various disability symptoms. The treatment protocol has been explored for a long time, but no consensus has been reached. PATIENT CONCERNS: Here, we report the case of a 19-year-old male suffering with nutcracker syndrome, including left-sided flank pain and intermittent gross hematuria. DIAGNOSES: The patient was diagnosed with renal nutcracker syndrome, and the pressure gradient between the left renal vein and inferior vena cava was >5 mm Hg. INTERVENTIONS: The patient underwentrobotic-assisted combined transposition of left renal vein and gonadal vein. OUTCOMES: Flank pain and gross hematuria ceased spontaneously after surgery without occurrence. LESSONS: Robotic-assisted combined transposition of the left renal vein and gonadal vein is a safe and promising option for this condition.

Topical and intravenous administration of human umbilical cord mesenchymal stem cells in patients with diabetic foot ulcer and peripheral arterial disease: a phase I pilot study with a 3-year follow-up.

BACKGROUND: Diabetic foot ulcer (DFU) is a serious chronic complication of diabetes mellitus that contributes to 85% of nontraumatic lower extremity amputations in diabetic patients. Preliminary clinical benefits have been shown in treatments based on mesenchymal stem cells for patients with DFU or peripheral arterial disease (PAD). However, the long-term safety and benefits are unclear for patients with both DFU and PAD who are not amenable to surgical revascularization. METHODS: In this phase I pilot study, 14 patients with PAD and incurable DFU were enrolled to assess the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) administration based on conservative treatments. All patients received topical and intravenous administrations of hUC-MSCs at a dosage of 2 × 105 cells/kg with an upper limit of 1 × 107 cells for each dose. The adverse events during treatment and follow-up were documented for safety assessments. The therapeutic efficacy was assessed by ulcer healing status, recurrence rate, and 3-year amputation-free rate in the follow-up phase. RESULTS: The safety profiles were favorable. Only 2 cases of transient fever were observed within 3 days after transfusion and considered possibly related to hUC-MSC administration intravenously. Ulcer disclosure was achieved for more than 95% of the lesion area for all patients within 1.5 months after treatment. The symptoms of chronic limb ischaemia were alleviated along with a decrease in Wagner scores, Rutherford grades, and visual analogue scale scores. No direct evidence was observed to indicate the alleviation of the obstruction in the main vessels of target limbs based on computed tomography angiography. The duration of rehospitalization for DFU was 2.0 ± 0.6 years. All of the patients survived without amputation due to the recurrence of DFU within 3 years after treatments. CONCLUSIONS: Based on the current pilot study, the preliminary clinical benefits of hUC-MSCs on DFU healing were shown, including good tolerance, a shortened healing time to 1.5 months and a favorable 3-year amputation-free survival rate. The clinical evidence in the current study suggested a further phase I/II study with a larger patient population and a more rigorous design to explore the efficacy and mechanism of hUC-MSCs on DFU healing. TRIAL REGISTRATION: The current study was registered retrospectively on 22 Jan 2022 with the Chinese Clinical Trial Registry (ChiCTR2200055885), http://www.chictr.org.cn/showproj.aspx?proj=135888.

Identification of PLAUR-related ceRNA and immune prognostic signature for kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) represents one of the most fatal cancers, usually showing malignant progression and a high tumor recurrence rate. The urokinase-type plasminogen activator receptor (PLAUR) plays a critical role in the initiation and progression of several cancers, including KIRC. However, the function and mechanism of PLAUR in patients with KIRC are still unclear and require further investigation. In the present study, we first explored the expression profile and prognostic values of PLAUR in pan-cancer based on The Cancer Genome Atlas and Genotype-Tissue Expression databases. PLAUR was upregulated in multiple cancers and was significantly associated with poor overall survival and disease-free survival only in patients with KIRC. Subsequently, the PVT1/SNHG15-hsa-miR-532-3p axis was identified as the most potential upstream regulatory network of PLAUR in KIRC. In addition, PLAUR expression was closely associated with tumor-infiltrating immune cells, tumor immunity biomarkers, and immunomodulator expression. Furthermore, we constructed a multiple-gene risk prediction signature according to the PLAUR-related immunomodulators (PRIs). A prognostic nomogram was then developed to predict the 1-, 3-, and 5-year survival probabilities of individuals. In conclusion, our study identified the PVT1/SNHG15-hsa-miR-532-3p-PLAUR axis and a prognostic signature of PRIs, which could be a reference for future clinical research.

Fine Tuning of Multiphoton AIE Emission Behavior, Organelle Targeting, and Fluorescence Lifetime Imaging of Terpyridine Derivatives by Alkyl Chain Engineering.

In this work, a series of multiphoton terpyridine agents (ZA, ZA-Mex, and ZA-Hex) for fluorescence lifetime imaging microscopy (FLIM) are designed and synthesized. The results from photophysical property research reveal that ZA-Hex, as an N-hexylated terpyridine salt, has stronger three-photon aggregation-induced emission (AIE) properties compared to ZA-Mex due to enhanced intramolecular charge transfer (ICT) performance. All three terpyridine derivatives possess suitable fluorescence intensities and stable fluorescence lifetimes under different pH conditions (pH = 4.0-8.0), thereby performing multiphoton fluorescence lifetime imaging. For biological imaging applications, it is found that ZA shows good lipid droplet (LD) turn-on fluorescence performance, and ZA-Hex could easily accumulate in mitochondria with high specificity. This is the first report of terpyridine salts as three-photon AIE probes used for multiphoton FLIM imaging.

Development of a radiomics model to diagnose pheochromocytoma preoperatively: a multicenter study with prospective validation.

BACKGROUND: Preoperative diagnosis of pheochromocytoma (PHEO) accurately impacts preoperative preparation and surgical outcome in PHEO patients. Highly reliable model to diagnose PHEO is lacking. We aimed to develop a magnetic resonance imaging (MRI)-based radiomic-clinical model to distinguish PHEO from adrenal lesions. METHODS: In total, 305 patients with 309 adrenal lesions were included and divided into different sets. The least absolute shrinkage and selection operator (LASSO) regression model was used for data dimension reduction, feature selection, and radiomics signature building. In addition, a nomogram incorporating the obtained radiomics signature and selected clinical predictors was developed by using multivariable logistic regression analysis. The performance of the radiomic-clinical model was assessed with respect to its discrimination, calibration, and clinical usefulness. RESULTS: Seven radiomics features were selected among the 1301 features obtained as they could differentiate PHEOs from other adrenal lesions in the training (area under the curve [AUC], 0.887), internal validation (AUC, 0.880), and external validation cohorts (AUC, 0.807). Predictors contained in the individualized prediction nomogram included the radiomics signature and symptom number (symptoms include headache, palpitation, and diaphoresis). The training set yielded an AUC of 0.893 for the nomogram, which was confirmed in the internal and external validation sets with AUCs of 0.906 and 0.844, respectively. Decision curve analyses indicated the nomogram was clinically useful. In addition, 25 patients with 25 lesions were recruited for prospective validation, which yielded an AUC of 0.917 for the nomogram. CONCLUSION: We propose a radiomic-based nomogram incorporating clinically useful signatures as an easy-to-use, predictive and individualized tool for PHEO diagnosis.

Impaired bone marrow microenvironment and stem cells in transfusion-dependent beta-thalassemia.

Beta-thalassemia (BT) is a hereditary disease caused by abnormal hemoglobin synthesis with consequent ineffective erythropoiesis. Patients with thalassemia major are dependent on long-term blood transfusions with associated long-term complications such as iron overload (IO). This excess iron can result in tissue damage, impaired organ function, and increased morbidity. Growing evidence has demonstrated that IO contributes to impairment of the bone marrow (BM) microenvironment that largely impacts the function of BM mesenchymal stem cells, hematopoietic stem cells, and endothelial cells. In this article, we review recent progress in the understanding of iron metabolism and the perniciousness induced by IO. We highlight the importance of understanding the cross-talk between BM stem cells and the BM microenvironment, particularly the pathological effect of IO on BM stem cells and BT-associated complications. We also provide an update on recent novel therapies to cure transfusion-dependent beta-thalassemia and iron overload-induced complications for their future clinical application.

Coexpression of TLR9 and VEGF-C is associated with lymphatic metastasis in prostate cancer.

Prostate cancer (PCa) is one of the most frequent cancers in men, and its biomolecular targets have been extensively studied. This study aimed to analyze the expression of toll-like receptor 9 (TLR9) and vascular endothelial growth factor C (VEGF-C) and the clinical value of the coexpression of TLR9 and VEGF-C in PCa. We retrospectively evaluated 55 patients with clinically localized, intermediate-risk, or high-risk PCa who underwent laparoscopic radical prostatectomy (LRP) and extended pelvic lymph node dissection (ePLND) without neoadjuvant hormonal therapy at a single institution from June 2013 to December 2016. In all 55 patients, the median number of lymph nodes (LNs) resected was 23 (range: 18-31), and a total of 1269 LNs were removed, of which 78 LNs were positive. Seventeen patients had positive LNs, with a positive rate of 30.9%. In addition, the immunohistochemical results in the above patients revealed that high TLR9 expression was correlated with higher Gleason score (GS) (P = 0.049), increased LN metastasis (P = 0.004), and more perineural invasion (PNI) (P = 0.033). Moreover, VEGF-C expression was associated with GS (P = 0.040), pathological stage (pT stage) (P = 0.022), LN metastasis (P = 0.003), and PNI (P = 0.001). Furthermore, a significant positive correlation between TLR9 and VEGF-C was found (P < 0.001), and the TLR9/VEGF-C phenotype was associated with LN metastasis (P = 0.047). Collectively, we propose that TLR9 stimulation may promote LN metastasis in PCa cells through the upregulation of VEGF-C expression, thereby affecting the prognosis of PCa patients. Therefore, these markers may serve as valuable targets for the treatment of PCa.

Bone Marrow Mesenchymal Stem Cells-Derived Exosomal miR-425-5p Inhibits Acute Myeloid Leukemia Cell Proliferation, Apoptosis, Invasion and Migration by Targeting WTAP.

INTRODUCTION: Acute myeloid leukemia (AML) is a predominant blood malignancy with high mortality and severe morbidity. AML is affected by microRNAs (miRNAs) loaded in exosomes derived from bone marrow mesenchymal stem cells (BM-MSCs). MiR-425-5p has been reported to participate in different cancer models. However, the function of BM-MSCs-derived exosomal miR-425-5p in AML is unclear. METHODS: The expression of miR-425-5p was measured by qRT-PCR in clinical AML samples. The immunophenotype of BM-MSCs was analyzed using antibodies against CD44, CD90, and CD105. The exosome was isolated from BM-MSCs. The effect of BM-MSCs-derived exosomal miR-425-5p on AML was analyzed by CCK-8 assay, Edu assay, transwell assay, flow cytometry in AML cells. qRT-PCR, luciferase reporter gene assay and Western blot analysis were also conducted in AML cells. RESULTS: The expression levels of miR-425-5p were decreased in CD34 + CD38-AML cells from primary AML patients compared to that from the bone marrow of healthy cases, and were reduced in exosomes from AML patients compared that from healthy cases. Similarly, miR-425-5p was also down-regulated in AML cell lines compared with BM-MSCs. MiR-425-5p was able to express in exosomes from BM-MSCs. CCK-8, Edu, transwell assay and flow cytometry analysis revealed that BM-MSCs-derived exosomal miR-425-5p significantly inhibited cell viability, Edu positive cells, invasion and migration, and induced apoptosis of AML cells. Meanwhile, the expression levels of cleaved PARP and cleaved caspase3 were increased by BM-MSCs-derived exosomal miR-425-5p in cells. MiR-425-5p inhibited the expression of Wilms tumor 1-associated protein (WTAP). Moreover, overexpression of WTAP could reverse the miR-425-5p-induced inhibition effect on AML cell proliferation, apoptosis, migration and invasion. CONCLUSION: BM-MSCs-derived exosomal miR-425-5p inhibits proliferation, invasion and migration of AML cells and induced apoptosis of AML cells by targeting WTAP. Therapeutically, BM-MSCs-derived exosomal miR-425-5p may serve as a potential target for AML therapy.

MicroRNA­93 knockdown inhibits acute myeloid leukemia cell growth via inactivating the PI3K/AKT pathway by upregulating DAB2.

Acute myeloid leukemia (AML) is associated with a poor prognosis in elderly adults and currently lacks optimal treatment strategies. MicroRNAs (miRNAs or miRs) have increasingly been reported to be associated with AML progression; however, the mechanisms of action of miR­93 in AML with the involvement of disabled 2 (DAB2) are currently unknown. In the present study, miR­93 expression was assessed in patients with AML and in AML cell lines. The association between miR­93 expression and the pathological characteristics of patients with AML was analyzed. AML cells were then transfected to knockdown or overexpress miR­93 in order to elucidate its function in AML progression. The target gene of miR­93 was assessed using a dual­luciferase reporter gene assay. The expression levels of miR­93, DAB2 and phosphatidylinositol 3­kinase (PI3K)/protein kinase B (AKT) pathway­related proteins were measured and in vivo experiments were conducted to confirm the results. It was observed that miR­93 was highly expressed in patients with AML and in AML cells. The knockdown of miR­93 in HL­60 cells inhibited AML cell proliferation and resistance to apoptosis, while the overexpression of miR­93 in THP­1 cells led to contrasting results. Moreover, miR­93 targeted DAB2 to inactivate the PI3K/AKT pathway, and the overexpression of DAB2 reversed the effects of miR­93 on THP­1 cell growth. Tumor volume, tumor weight, and the positive expression of Ki67, survivin and p53 were increased in THP­1 cells overexpressing miR­93. On the whole, the present study demonstrates that miR­93 is highly expressed in AML cells, and that the suppression of miR­93 inhibits AML cell growth by targeting DAB2 and inhibiting the PI3K/AKT pathway.

MiR-335-3p inhibits cell proliferation and induces cell cycle arrest and apoptosis in acute myeloid leukemia by targeting EIF3E.

Here, we aimed to investigate the biological roles and the regulatory mechanisms of miR-335-3p in acute myeloid leukemia (AML). We first found miR-335-3p was significantly downregulated in blood samples from leukemia patients and cell lines using reverse transcription quantitative polymerase chain reaction. Through CCK-8 assay and flow cytometry, we observed that miR-335-3p overexpression significantly inhibited cell proliferation and induced cell cycle G0/G1 arrest and apoptosis in AML cell lines (THP-1 and U937). Moreover, miR-335-3p directly targets EIF3E and negatively regulated its expression. More importantly, EIF3E overexpression reversed the effects of miR-335-3p on cell proliferation, G1/S transition, and apoptosis. Furthermore, miR-335-3p overexpression obviously downregulated the expression of CDK4, Cyclin D1, and Bcl-2, while upregulated the expression of p21 and Bad, which were significantly rescued by the cotransfection of pcDNA3.1-EIF3E. Collectively, our study proposes that miR-335-3p/EIF3E axis could be a promising therapeutic target to mitigate the progression of AML.

A Regulatory Loop Involving Notch and Wnt Signaling Maintains Leukemia Stem Cells in T-Cell Acute Lymphoblastic Leukemia.

Leukemia-initiating cells play critical role in relapse, resistance to therapies and metastases but the mechanism remains largely elusive. We report that ß-catenin is over-expressed in almost all T-ALL patients and flow sorted ß-cateninhigh fractions are highly resistant to therapy, leading to liver metastases in nude mice as well as dysregulated lncRNAs. Pharmacological inhibition through XAV-939 as well as si-RNA mediated inhibition of ß-catenin is initially effective in re-sensitization to therapy, however, prolonged inhibition shifts dependency from ß-catenin to Notch signaling, with particularly high levels of receptors Notch 1 and Notch 2. The results are verifiable in a cohort of T-ALL patients comprising of responders vs. those who have progressed, with ß-catenin, Notch 1 and Notch 2 elevated in progressed patients. Further, in patients-derived cells, silencing of Notch 1 or Notch 2 does not counter resistance to ß-catenin inhibition, rather pharmacological pan-Notch inhibition is needed to overcome resistance and its effect on in vitro tumor sphere formations as well as in vivo liver metastases. Thus, wnt and Notch signaling are part of a regulatory loop mutually compensating for each other in T-ALL, while ensuring the maintenance of stem cell phenotype.

HDAC8 promotes daunorubicin resistance of human acute myeloid leukemia cells via regulation of IL-6 and IL-8.

The chemoresistance is one of the major challenges for acute myeloid leukemia (AML) treatment. We found that the expression of histone deacetylase 8 (HDAC8) was increased in daunorubicin (DNR) resistant AML cells, while targeted inhibition of HDAC8 by its specific siRNA or inhibitor can restore sensitivity of DNR treatment . Further, targeted inhibition of HDAC8 can suppress expression of interleukin 6 (IL-6) and IL-8. While recombinant IL-6 (rIL-6) and rIL-8 can reverse si-HDAC8-resored DNR sensitivity of AML cells. Mechanistical study revealed that HDAC8 increased the expression of p65, one of key components of NF-κB complex, to promote the expression of IL-6 and IL-8. It might be due to that HDAC8 can directly bind with the promoter of p65 to increase its transcription and expression. Collectively, our data suggested that HDAC8 promotes DNR resistance of human AML cells via regulation of IL-6 and IL-8.

Comparing intravenous peramivir with oral oseltamivir for patients with influenza: a meta-analysis of randomized controlled trials.

BACKGROUND: The study was to compare the efficacy between IV peramivir and oral oseltamivir treatments in patients with influenza. METHODS: The PubMed, EMBASE, Scopus, ClinicalTrials.gov, and Cochrane Library databases were searched for studies published before January 2020. RESULTS: The meta-analysis was conducted to calculate the pooled effect size by using a random-effects model. Seven randomized controlled trials (RCTs) including 1,138 patients were reviewed. The incidence of total complications revealed no significant difference between 600 mg IV peramivir (P600) and 75 mg oral oseltamivir (O75) treatments (2.8% vs. 4.1%; risk ratio [RR] = 0.70; 95% confidence interval [CI]: 0.36-1.38). The incidence of pneumonia was not significantly different between the P600 and O75 treatment groups (2.2% vs. 2.7%; RR = 0.74; 95% CI: 0.37-1.51). Regarding the time to the alleviation of symptoms, no difference was found in P600 and O75 treatment (MD = -3.00; 95% CI: -11.07 to 5.06). The rate of fever clearance in 24 h and the time to fever resolution were not statistically different between the IV peramivir and oral oseltamivir treatments (at different dosages) groups. CONCLUSIONS: The treatment of influenza with IV peramivir or oral oseltamivir had similar clinical efficacy.