[Long-term hypomethylating agents in patients with myelodysplastic syndromes: a multi-center retrospective study].

Objective: To evaluate the efficacy and safety of hypomethylating agents (HMA) in patients with myelodysplastic syndromes (MDS) . Methods: A total of 409 MDS patients from 45 hospitals in Zhejiang province who received at least four consecutive cycles of HMA monotherapy as initial therapy were enrolled to evaluate the efficacy and safety of HMA. Mann-Whitney U or Chi-square tests were used to compare the differences in the clinical data. Logistic regression and Cox regression were used to analyze the factors affecting efficacy and survival. Kaplan-Meier was used for survival analysis. Results: Patients received HMA treatment for a median of 6 cycles (range, 4-25 cycles) . The complete remission (CR) rate was 33.98% and the overall response rate (ORR) was 77.02%. Multivariate analysis revealed that complex karyotype (P=0.02, OR=0.39, 95%CI 0.18-0.84) was an independent favorable factor for CR rate. TP53 mutation (P=0.02, OR=0.22, 95%CI 0.06-0.77) was a predictive factor for a higher ORR. The median OS for the HMA-treated patients was 25.67 (95%CI 21.14-30.19) months. HMA response (P=0.036, HR=0.47, 95%CI 0.23-0.95) was an independent favorable prognostic factor, whereas complex karyotype (P=0.024, HR=2.14, 95%CI 1.10-4.15) , leukemia transformation (P<0.001, HR=2.839, 95%CI 1.64-4.92) , and TP53 mutation (P=0.012, HR=2.19, 95%CI 1.19-4.07) were independent adverse prognostic factors. There was no significant difference in efficacy and survival between the reduced and standard doses of HMA. The CR rate and ORR of MDS patients treated with decitabine and azacitidine were not significantly different. The median OS of patients treated with decitabine was longer compared with that of patients treated with azacitidine (29.53 months vs 20.17 months, P=0.007) . The incidence of bone marrow suppression and pneumonia in the decitabine group was higher compared with that in the azacitidine group. Conclusion: Continuous and regular use of appropriate doses of hypomethylating agents may benefit MDS patients to the greatest extent if it is tolerated.

[Comparison of efficacy and safety between domestic immune checkpoint inhibitors and pembrolizumab in the treatment of driver gene-negative advanced non-small cell lung cancer].

Objective: To compare the efficacy and safety of domestic immune checkpoint inhibitors and pembrolizumab in the treatment of driver gene-negative advanced non-small cell lung cancer. Methods: A retrospective analysis was conducted on the data of 1 241 patients with driver gene-negative, unresectable stage ⅢB to Ⅳ non-small cell lung cancer who were treated at the Hunan Cancer Hospital from January 1, 2017 to October 1, 2022. All patients received monotherapy or combination therapy with domestic immune checkpoint inhibitors or pembrolizumab. Among the 1 241 patients, there were 1 066 males and 175 females, with an age range of 14 to 84 years and a median age of 62 years. Among them, 67 patients received monotherapy with domestic immune checkpoint inhibitors, 695 patients received combination therapy with domestic immune checkpoint inhibitors, 102 patients received monotherapy with pembrolizumab, and 377 patients received combination therapy with pembrolizumab. The efficacy and safety of domestic immune checkpoint inhibitors and pembrolizumab monotherapy or combination therapy were compared. Results: In the immune checkpoint inhibitor monotherapy group, the objective response rate (ORR) using domestic immune checkpoint inhibitors and pembrolizumab was 43.3%(29/67) and 44.1%(45/102), respectively, and the disease control rate (DCR) was 79.1%(53/67) and 84.3%(86/102), respectively, with no statistically significant differences (both P>0.05). In the immune combination therapy group, the ORR using domestic immune checkpoint inhibitors and pembrolizumab was 60.9%(423/695) and 62.9%(237/377), respectively, and the DCR was 92.9%(646/695) and 91.0%(343/377), respectively, with no statistically significant differences (both P>0.05). In the immune checkpoint inhibitor monotherapy group, the median progression-free survival (PFS) using domestic immune checkpoint inhibitors and pembrolizumab was 9.0 (95%CI: 3.0-15.0) months and 7.4 (95%CI: 4.8-9.8) months, respectively, with no statistically significant differences (P=0.660). The median overall survival (OS) was 27.0 (95%CI: 25.0-29.0) months and 22.0 (95%CI: 17.1-26.9) months, respectively, with no statistically significant differences (P=0.673). In the immune combination therapy group, the median PFS using domestic immune checkpoint inhibitors and pembrolizumab was 9.0 (95%CI: 8.2-9.8) months and 10.5 (95%CI: 9.0-12.0) months, respectively, with no statistically significant differences (P=0.186). The median OS was 24.0 (95%CI: 19.1-28.9) months and 26.0 (95%CI: 21.3-30.7) months, respectively, with no statistically significant differences (P=0.359). The incidence of grade 1-2 reactive capillary proliferation of the skin in the domestic immune checkpoint inhibitor group and pembrolizumab group was 14.0% (107/762) and 0, respectively. The incidence of grade≥3 reactive capillary proliferation of the skin was 1.0% (7/762) and 0, respectively, with statistically significant differences (both P<0.05). No statistically significant differences were observed in other adverse reactions (all P>0.05). Conclusions: The efficacy of domestically produced immune checkpoint inhibitors is comparable to that of pembrolizumab in the treatment of driver gene-negative advanced non-small cell lung cancer. There is little difference in safety, except for the specific difference in domestically produced immune checkpoint inhibitor, which has a unique risk of reactive cutaneous capillary endothelial proliferation.

[Analysis of clinical and genetic variation in neonatal intrahepatic cholestasis caused by citrin deficiency].

Objective: To investigate the clinical phenotype and gene variation conditions in neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), so as to provide a basis for genetic counseling and clinical diagnosis and treatment of the family. Methods: 11 cases of neonatal intrahepatic cholestasis who visited the Children's Hospital Affiliated to Zhengzhou University between February 2019 and March 2021 were selected as the study subjects. High-throughput sequencing technology was used to detect the gene variation condition in 11 neonatal patients and 100 normal control neonates. The suspicious loci and family members were verified by Sanger sequencing and QPCR technology. Results: All 11 children with NICCD had different degrees of jaundice and liver damage symptoms, combined with coagulation dysfunction and anemia (n = 7), cardiac malformation (n = 2), elevated myocardial enzymes (n = 4), hyperlipidemia (n = 1), hyperkalemia (n = 1), persistent diarrhea (n = 3), developmental delay (n = 1). A total of 10 different types of SLC25A13 gene mutations were detected in 11 cases, including three frameshift mutations, two splicing changes, two missense mutations, one intron insertion, one nonsense mutation, and one heterozygous deletion. After reviewing literature and databases, c.1878delG(p.I627Sfs*73) and exon11 deletion were novel mutations that had not been reported at home or abroad. Conclusion: The clinical features of NICCD are non-specific, and genetic testing aids in the early and accurate diagnosis of the disease, providing an important basis for clinical treatment and genetic counseling for family members. In addition, the detection of novel mutation sites has enriched the SLC25A13 gene variation spectrum.

[Impact of sinonasal anatomic changes after endoscopic anterior skull base surgery on nasal airflow and air conditioning: a computational fluid dynamics study].

Objective: To analyze the impact of the sinonasal anatomic changes after endonasal endoscopic anterior skull base surgery on the nasal airflow and heating and humidification by computational fluid dynamics (CFD), and to explore the correlation between the postoperative CFD parameters and the subjective symptoms of the patients. Methods: The clinical data in the Rhinology Department of the First Affiliated Hospital of Zhengzhou University from 2016 to 2021 were retrospectively analyzed. The patients received the endoscopic resection of the anterior skull base tumor were selected as the case group, and the adults whose CT scans had no sinonasal abnormalities were chosen as the control group. The CFD simulation was performed on the sinonasal models after reconstructed from the patients' sinus CT images during the post-surgical follow-up. All the patients were asked to complete the Empty Nose Syndrome 6-Item Questionnaire (ENS6Q) to assess the subjective symptoms. The comparison between two independent groups and the correlation analysis were carried out by using the Mann-Whitney U test and the Spearman correlation test in the SPSS 26.0 software. Results: Nineteen patients (including 8 males and 11 females, from 22 to 67 years old) in the case group and 2 patients (a male of 38 years old and a female of 45 years old) in the control group were enrolled in this study. After the anterior skull base surgery, the high-speed airflow moved to the upper part of the nasal cavity, and the lowest temperature shifted upwards on the choana. Comparing with the control group, the ratio of nasal mucosal surface area to nasal ventilation volume in the case group decreased [0.41 (0.40, 0.41) mm-1 vs 0.32 (0.30, 0.38) mm-1; Z=-2.04, P=0.041], the air flow in the upper and middle part of the nasal cavity increased [61.14 (59.78, 62.51)% vs 78.07 (76.22, 94.43)%; Z=-2.28, P=0.023], the nasal resistance decreased [0.024 (0.022, 0.026) Pa·s/ml vs 0.016 (0.009, 0.018) Pa·s/ml; Z=-2.29, P=0.022], the lowest temperature in the middle of the nasal cavity decreased [28.29 (27.23, 29.35)℃ vs 25.06 (24.07, 25.50)℃; Z=-2.28, P=0.023], the nasal heating efficiency decreased [98.74 (97.95, 99.52)% vs 82.16 (80.24, 86.91)%; Z=-2.28, P=0.023], the lowest relative humidity decreased [(79.62 (76.55, 82.69)% vs 73.28 (71.27, 75.05)%; Z=-2.28, P=0.023], and the nasal humidification efficiency decreased [99.50 (97.69, 101.30)% vs 86.09 (79.33, 87.16)%; Z=-2.28, P=0.023]. The ENS6Q total scores of all patients in the case group were less than 11 points. There was a moderate negative correlation between the proportion of the inferior airflow in the post-surgical nasal cavity negatively and the ENS6Q total scores (rs=-0.50, P=0.029). Conclusions: The sinonasal anatomic changes after the endoscopic anterior skull base surgery alter the nasal airflow patterns, reducing the efficiency of nasal heating and humidification. However, the post-surgical occurrence tendency of the empty nose syndrome is weak.

[Prognostic factors of cyclosporine A combined with danazol with or without thalidomide in myelodysplastic syndrome treatment with low-percentage bone marrow blasts].

Objective: To explore the outcome of cyclosporine A (CsA) combined with danazol with or without thalidomide regimen for myelodysplastic syndrome (MDS) with low-percentage bone marrow blasts and predictive factors for treatment response. Methods: Data of 115 subjects who were newly diagnosed with primary MDS with low-percentage bone marrow blasts and were treated with CsA combined with danazol with or without thalidomide from December 2011 to December 2019 in our center were collected. Their clinical features, efficacy, and predictive factors of efficacy were retrospectively analyzed. A model for predicting this response was developed. Results: A total of 55 subjects responded (47.8%) , including 11 complete responses and 44 hematologic improvements. Fifty-two patients (52/105, 49.5%) achieved erythrocyte response; 35 (35/86, 40.7%) , platelet response; and 14 (14/40, 35%) , neutrophil response. Of 29 subjects (24.1%) , 7 who were red blood cell (RBC) transfusion-dependent became independent of transfusion. The median response duration was 20 months (range, 3-84 months) . In the univariate analysis, patients <0 years had a higher response rate than those ≥60 years (52.5% vs 22.2%, P=0.018) . Contrarily, the response rate was substantially decreased in patients with RBC transfusion dependence compared with those without RBC transfusion dependence (24.1% vs 55.8%, P=0.003) , as well as in patients with the mutated U2AF1 compared with those with the wild-type U2AF1 (26.1% vs 53.2%, P=0.020) . In multivariable analyses, age <0 years (OR=4.302, 95% CI 1.245-14.820, P=0.021) , RBC transfusion dependence (OR=3.774, 95% CI 1.400-10.177, P=0.009) , and U2AF1 mutation (OR=3.414, 95% CI 1.168-9.978, P=0.025) were significantly correlated with response. Variables that independently predicted the response were combined to generate the predictive model. According to the model, the overall response rates of patients with 0, 1, 2, and 3 risk factors were 65%, 30%-35%, 10%-15%, and 3%, respectively. Conclusion: CsA combined with danazol with or without thalidomide regimen could improve cytopenia symptoms in patients with MDS with low-percentage bone marrow blasts. At age <60 years, no transfusion dependence of RBC and wild-type U2AF1 mutation is a favorable prognostic factor.

[Perioperative safety and feasibility of simultaneous off-pump coronary artery bypass grafting with non-cardiac surgical procedures of moderate-to-severe severity].

Objective: To examine the perioperative safety and feasibility of simultaneous off-pump coronary artery bypass grafting (OPCAB) with non-cardiac surgical procedures of moderate-to-severe severity. Methods: The perioperative results of 54 patients underwent simultaneous OPCAB with non-cardiac surgical procedures from September 2013 to January 2019 at Department of Cardiac Surgery, Peking University First Hospital were assessed retrospectively. There were 46 males and 8 females, aging (65.8±8.8) years (range: 41 to 85 years). All simultaneous non-cardiac surgical procedures, including vascular (n=1), thoracic (n=26), general (n=12) and urologic surgical procedures (n=15), were assessed to be of moderate-to-severe grade by operative severity scoring system. Perioperative results were compared between the OPCAB patients who underwent simultaneous non-cardiac surgical procedures (n=54) and 1∶2 matched patients who underwent isolated OPCAB performed most recently by the same cardiac team with similar procedures accordingly (n=108), using t test, Mann-Whitney U test, χ2 test or Fisher exact test. Results: All baseline factors were matched between the two groups, with no significant difference on European system for cardiac operative risk evaluation (EuroSCORE) Ⅱ (1.185(0.758)% vs. 1.215(0.905)%, Z=‒0.036, P=0.972). No perioperative death was observed in the two groups. Although patients underwent simultaneous non-cardiac surgical procedures showed prolonged operation duration time ((324.9±97.1) minutes vs. (166.7±36.7) minites, t=11.564, P<0.01) and increased intraoperaive blood loss ((462.2±269.6) ml vs. (304.5±177.8) ml, t=3.866, P<0.01), primary postoperative complications, including perioperative myocardial infarction, atrial fibrillation, perioperative stroke, acute renal failure, wound infection, and bleeding reoperation did not show significant differences between the two groups (all P>0.05), while total blood transfusion volume, mechanical ventilation time and intensive care unit residence time also showed no significant differences between the two groups (all P>0.05). Conclusion: Simultaneous OPCAB with non-cardiac surgical procedures of moderate-to-severe severity in patients with operative indications are safe and feasible, and are not associated with increased postoperative risks when compared with isolated OPCAB.

Long noncoding RNA SOX2OT maintains the stemness of pancreatic cancer cells by regulating DEK via interacting with miR-200a/141.

The article "Long noncoding RNA SOX2OT maintains the stemness of pancreatic cancer cells by regulating DEK via interacting with miR-200a/141, by C.-S. Liu, Q. Zhou, Y.-D. Zhang, Y. Fu, published in Eur Rev Med Pharmacol Sci 2020; 24 (5): 2368-2379-DOI: 10.26355/eurrev_202003_20504-PMID: 32196588" has been withdrawn from the authors stating that "to validate the effect of lncRNA-SOX2OT, we constructed SOX2OT overexpressed cells using lentiviral vector with -IRES2-EGFP to easily visualize the transfection efficiency. Therefore, the stably transfected cells were carrying the green fluorescence. However, during our Flow cytometry assay, we took PC cells (Control) with no fluorescence to standardize our equipment and measured the negative control (NC) and overexpressed-Sox2ot (oe-Sox2ot) according to the manufacturer's guidance, without removing the disturbance that the green fluorescence caused. This means that, despite having performed the standard assay, the results obtained in Figure 2D were wrong and unscientific". The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/20504.

[Molecular features and prognostic value of RAS mutations in patients with myelodysplastic syndromes].

Objective: To explore the molecular features and prognostic value of RAS mutations in patients with myelodysplastic syndromes (MDS) . Methods: 112-gene targeted sequencing was conducted to detect RAS mutations in 776 patients with newly diagnosed primary MDS from December 2011 to December 2018. The mutual exclusivity and co-occurrence in gene mutations and clonal architecture were explored. Moreover, the prognostic significance of RAS mutations in MDS was analyzed. Results: RAS gene mutations were found in 52 (6.7% ) cases, 38 (4.9% ) of whom harbored NRAS mutation, 18 (2.3% ) KRAS mutation, and 4 (0.5% ) both NRAS and KRAS mutations. All the NRAS mutations and 65% of the KRAS mutations were located in codons 12, 13, and 61. PTPN11, FLT3, U2AF1, RUNX1, WT1, ETV6, and NPM1 mutations were enriched in patients with RAS mutations (Q<0.05) . Around 80% of RAS mutations represented subclonal lesions in patients who harbored at least two different mutations. Patients with RAS mutations were more frequently diagnosed with MDS with excess blast (MDS-EB) (82.7% vs. 35.2% , P<0.001) and had higher levels of white blood cell count (4.33×10(9)/L vs. 2.71×10(9)/L, P<0.001) , neutrophil absolute count (2.13×10(9)/L vs. 1.12×10(9)/L, P<0.001) , and bone marrow blast percentage (7% vs. 2% , P<0.001) but lower levels of platelet count (48×10(9)/L vs. 62×10(9)/L, P=0.048) . RAS mutations were correlated with higher-risk categories in the Revised International Prognostic Scoring System (IPSS-R) (71.1% vs. 37.9% , P<0.001) . The median overall survival of patients with NRAS mutations was shorter than the others (P=0.011) , while the significance was lost in the multivariable model. Conclusion: RAS gene mutations always occurred in the late-stage MDS and co-occurred with other signal transduction- and transcription factor-related gene mutations. PTPN11, a RAS pathway-related gene, is an independent poor prognostic factor in MDS patients.

[Features and clinical significance of gene mutations in patients with myelodysplastic syndromes with ring sideroblasts].

Objective: To explore the features and clinical significance of gene mutations in patients with myelodysplastic syndromes with ring sideroblasts (MDS-RS) . Methods: A total of 255 newly diagnosed primary MDS-RS patients were retrospectively reviewed from our center from January2001 to June 2019. SF3B1 gene mutations were detected by Sanger sequencing in 129 patients, and next generation sequencing (NGS) was performed in the other 126 patients using a set of selected 112-genes. Results: A total of 193 (75.7%) patients presented with SF3B1 mutation, predominantly mutant at amino acid position 700 (K700E) (n=147, 76.2%) . Non-SF3B1 gene mutations were TET2 (16.7%) , ASXL1 (14.3%) , U2AF1 (11.1%) , TP53 (7.9%) , SETBP1 (6.3%) , and RUNX1 (6.3%) . RS 5%-<15% patients had a higher SETBP1 mutation frequency than RS≥15% patients (21.4% vs 4.5%, P=0.044) . Mutation frequencies of other genes were similar in both groups (all P>0.05) . SF3B1 variant allele frequencies (VAF) had positive correlation with marrow RS percentage but without statistical significance in RS 5%-<15% group (P=0.078, r=0.486) . SF3B1 mutant patients presented with higher marrow RS percentage compared with wild-type patients[40.0% (15.0%-80.0%) vs 25.5% (15.0%-82.0%) , P<0.001], and SF3B1 VAF positively correlated with RS percentage (P=0.009, rs=0.261) in RS≥15% group. Age, ANC, PLT, mean RBC corpuscular volume, RS percentage, IPSS-R cytogenetics, and IPSS-R risk score were significantly different between patients with SF3B1 mutations and wild-type SF3B1 (all P<0.05) . Multivariable survival analyses adjusted by age and IPSS-R cytogenetics revealed that SF3B1 mutation was an independent favorable prognostic factor (HR=0.265, 95% CI 0.077-0.917, P=0.036) , and TP53 mutation was an adverse variable independent of SF3B1 mutation (HR=6.272, 95% CI 1.725-22.809, P=0.005) . According to the mutant status of SF3B1 and TP53, MDS-RS patients were categorized into 4 groups, namely, with SF3B1 and TP53 mutation, with wild-type SF3B1 and TP53, with wild-type SF3B1 but TP53 mutation, and with SF3B1 mutation but wild-type TP53. There was a significant difference for OS among these 4 groups (P<0.001) . The former 3 groups showed no significant difference in OS in multiple comparisons. However, the SF3B1 mutation but wild-type TP53 group had a better OS than wild-type SF3B1 but TP53 mutation group and wild-type SF3B1 and TP53 group, whereas a similar OS compared with SF3B1 and TP53 mutation group. Conclusion: SF3B1 mutations were prevalent in MDS-RS patients with the most common mutation at amino acid position 700 (K700E) . SF3B1 mutation was an independent favorable prognostic variable, whereas TP53 mutation was an independent adverse variable. SF3B1 mutation could coordinate with TP53 mutation for more sophisticated prognosis stratification in MDS-RS patients.

Mettl3 regulates the proliferation, migration and invasion of glioma cells by inhibiting PI3K/Akt signaling pathway.

OBJECTIVE: Methyltransferase-like 3 (Mettl3), one of "writers" for N6-methyladenosine RNA methylation is determined to participate in a variety of cell biological functions. However, the functions of Mettl3 on tumor growth of glioma remain unknown. Here, we conducted a research to explore the contribution of Mettl3 in the progression of glioma. PATIENTS AND METHODS: To detect the expression level of RNAs, quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed. To access the relative level of proteins, Western blot was conducted. The proliferative ability of glioma cells was detected by CCK-8 assay and colony formation assay. The migration and invasion of glioma cells were determined by wound healing assay and transwell invasion assay. RESULTS: The expression of Mettl3 was significantly downregulated in tumor tissues compared to the adjacent normal tissues. The downregulation of Mettl3 led to the enhancement of glioma cell proliferation, migration, and invasion in vitro, and promoted the tumor growth of glioma cells in vivo. In addition, further investigation confirmed that Mettl3 plays critical roles in the development of glioma by targeting PI3K/Akt pathway. CONCLUSIONS: Our study proves that Mettl3 plays a critical role in the proliferation, migration, and invasion of glioma cells by inactivating PI3K/Akt signaling pathway, providing a novel mechanism of glioma tumorigenesis and raising a new target for the treatment of glioma.

Long noncoding RNA SOX2OT maintains the stemness of pancreatic cancer cells by regulating DEK via interacting with miR-200a/141.

OBJECTIVE: Long noncoding RNA sex determination region of Y chromosome (SRY)-related HMG-box (SOX) is involved in the development of various cancers. However, the molecular mechanism of SOXOT, an overlapping transcript of SOX, in pancreatic cancer (PC) is still undefined. We aimed to explore the epigenetic function of SOX2OT and its downstream factors in advanced PC. PATIENTS AND METHODS: The levels of SOX2OT, miRNA, and DEK proto-oncogene (DEK) in pancreatic cancer tissues and cell lines were evaluated by quantitative polymerase chain reaction (qPCR). The log-rank test was applied to evaluate the role of high SOX2OT levels in shortening the overall survival of pancreatic cancer patients. The Chi-squared test was made to assess the relation between SOX2OT expression and clinicopathological features of PC patients. Colony assay tested the cell proliferation of PC cells with SOX2OT knockdown. Flow cytometry and Western blotting were used to determine the stemness of tumor cells in vitro. The underlying regulatory mechanism between SOX2OT and miR-200a/141 was predicted by bioinformatics and verified by RNA transfection, qPCR, and Western blotting. Mice xenograft models were applied to determine the promoting effects of SOX2OT on PC in vivo. RESULTS: The expression of SOX2OT in PC tissues and cell lines is strongly elevated. High levels of SOX2OT expression are more likely to present in patients with advanced TNM stage, positive CD44, and poor overall survival. SOX2OT overexpression promotes proliferation and stemness maintaining of PC cells in vitro and boosts tumor growth in vivo. Furthermore, SOX2OT upregulates DEK expression by binding to miR-200a/141 as a competing endogenous RNA. CONCLUSIONS: DEK induced by SOXOT- miR-200a/141 axis may markedly promote stem cell property of PC, resulting in an advanced stage and inferior survival. These findings suggest the SOX2OT-DEK axis as a novel therapeutic target in PC.

[Mean corpuscular volume ≤100 fl was an independent prognostic factor in patients with myelodysplastic syndrome and bone marrow blast<5 percent].

Objective: To explore the prognostic effects of mean corpuscular volume (MCV) in patients with myelodysplastic syndromes (MDS) . Methods: 321 newly diagnosed, untransfused primary MDS patients who administered from December 2009 to December 2017 were enrolled. The association of MCV with prognosis and several clinical features and genetic mutations were analyzed. Results: Patients were divided into MCV≤100 fl (n=148) and MCV>100 fl (n=173) cohorts. Median overall survival of patients with MCV≤100 fl was shorter than their counterparts (27 months vs 72 months, P<0.001) . In subgroup analysis, MCV≤100 fl patients had worse survivals in bone marrow blast <5% cohort (34 months vs not reached, P=0.002) , but not so in ≥5 % cohort (17 months vs 20 months, P=0.078) . MCV≤100 fl was still an independent adverse variable (HR=1.890, 95%CI 1.007-3.548, P=0.048) after adjusting for clinical and laboratory variables and mutation topography in bone marrow blasts<5% cohort. In bone marrow blasts<5% cohort, patients with MCV≤100 fl had higher hemoglobin levels [90 (42-153) g/L vs 78.5 (28-146) g/L, P=0.015].The proportions of Revised International Prognostic Scoring System (IPSS-R) high/very high risks and poor/very poor IPSS-R karyotypes were higher in MCV≤100 fl cohort (28.8% vs 10.8%, P=0.003; 24.7% vs 12.9%, P=0.049) . MCV≤100 fl cohort had more genetic mutations than those with MCV>100 fl though without significance (0.988 vs 0.769, P=0.064) . Mutated SF3B1 was less frequently in MCV≤100 fl cohort (4.7% vs 15.4%, P=0.018) . Conclusion: MCV≤100 fl was an independent adverse variable after adjusting for clinical and laboratory variables and mutation topography in MDS patients with bone marrow blasts<5%.

[Genetic characteristics and prognostic values of RAS mutations in patients with myelofibrosis].

Objective: To explore the genetic characteristics, clinical features, and prognostic values of RAS mutations in patients with myelofibrosis (MF) . Methods: We analyzed 112-gene targeted sequencing data from 226 patients who had a diagnosis of either primary myelofibrosis (PMF) or post-polycythemia vera/post-essential thrombocythemia (post-PV MF and post-ET MF) from December 2011 to December 2019. A retrospective analysis of the genetic characteristics, clinical features, and prognosis of RAS mutations was performed. Results: Among 266 patients diagnosed PMF or post-PV/ET MF, RAS mutations were found in 14 (6.2%) cases, including 9 (4.0%) cases of NRAS mutations, 8 (3.5%) cases of KRAS mutations, and 3 (1.3%) cases of both NRAS and KRAS mutations. All of the NRAS mutations were located in codons 12 and 13. The median VAFs of RAS mutations were significantly lower than those of the driver mutations, confirming that they represent sub-clonal events that are acquired during the disease course. SETBP1, SRSF2, and MPL tended to be clustered with RAS mutations. Patients with RAS mutations had a higher number of additional oncogenic mutations (median, 3.36 vs 1.17, P<0.001) . RAS mutations had a statistically significant association with elevated monocyte cell counts (P=0.003) , lower platelet counts (P=0.026) , higher bone marrow blasts (P=0.022) , splenomegaly (P=0.005) , and very high-risk (VHR) karyotype abnormality percentage (P=0.031) . In univariate analysis, the OS of patients with NRAS mutations were significantly inferior in the entire MF and PMF cohorts (P=0.001, P=0.008) . In a multivariate model, NRAS retained an independent negative prognostic factor in PMF. Conclusion: RAS gene mutations were constantly related to elevated monocyte cell counts, lower platelet counts, higher bone marrow blasts, and VHR karyotype abnormality percentage that usually defined high-risk disease and often occurred as sub-clonal events. NRAS mutation is an independent poor prognostic factor in PMF.

Effect of miR-124 on neuronal apoptosis in rats with cerebral infarction through Wnt/ß-catenin signaling pathway.

OBJECTIVE: The aim of this study was to observe the influence of micro ribonucleic acid (miR)-124 on neuronal apoptosis in rats with cerebral infarction (CI), and to further investigate the underlying mechanism of miR-124 in CI occurrence and development. MATERIALS AND METHODS: A total of 60 adult male Wistar rats were randomly divided into the Sham group, the CI group and the CI + miR-124 mimics group using a random number table. The focal CI model was established using the suture-occluded method. After successful modeling, miR-124 mimics were stereotactically injected into the lateral ventricle of rats. 24 h after operation, the neurological function of rats in each group was scored using modified neurological severity score (mNSS). Meanwhile, the infarction area of brain tissues was evaluated by the triphenyl tetrazolium chloride (TTC) method. The protein expression levels of apoptosis-related genes, including B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), C-Caspase and T-Caspase, were detected via Western blotting. The expression and location of caspase-3 in brain tissues were detected via immunofluorescence staining. Moreover, the level of apoptosis in each group was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. In addition, the expression levels of the Wnt/ß-catenin signaling pathway-related proteins were detected via Western blotting. RESULTS: Polymerase Chain Reaction (PCR) results revealed that the expression level of miR-124 in the CI group was significantly decreased when compared with that of the Sham group (p<0.05). The mNSS and TTC staining results manifested that injection of miR-124 mimics could significantly reduce the CI-induced neurological deficits and CI area (p<0.05). At the same time, the levels of Bax and C-caspase/T-Caspase were significantly decreased, whereas the expression of Bcl-2 was remarkably increased after the injection of miR-124 mimics (p<0.05). Besides, the number of apoptotic cells in the CI + miR-124 mimic group was remarkably decreased (p<0.05). In addition, miR-124 mimics significantly activated the expression levels of Wnt and ß-catenin (p<0.05). CONCLUSIONS: The inhibitory effect of miR-124 on neuronal apoptosis in CI rats is probably related to the activation of the Wnt/ß-catenin signaling pathway. Furthermore, miR-124 is expected to be a target drug for the clinical treatment of CI.

Long non-coding RNA H19 regulates the development of gliomas through the Wnt/ß-catenin signaling pathway.

OBJECTIVE: We investigated the effects of long non-coding RNA (lncRNA) H19 on glioma cell proliferation, invasion, migration, and apoptosis and the underlying mechanisms. PATIENTS AND METHODS: H19 expression in glioma tissues, para-carcinoma tissues, and glioma cell lines was analyzed by Real-time polymerase chain reaction (RT-PCR). After transfecting U251 and U87MG cells with siRNA-H19, cell proliferation was detected by the cell counting kit-8 (CCK8) assay. Invasion and migration were detected by a transwell assay; cell cycle distribution and apoptosis were measured by flow cytometry analysis; Dvl2, GSK-3ß, cyclin D1, and ß-catenin expressions were detected by RT-PCR and Western blotting. RESULTS: H19 expression in glioma tissues was higher than that in para-carcinoma tissues and associated with poor prognosis in glioma patients. Cell proliferation, invasion, and migration significantly decreased, the percentage of glioma cells in G0/G1 significantly increased, the percentage of glioma cells in the S phase significantly decreased, and apoptosis significantly increased in U251 and U87MG cells transfected with siRNA-H19 compared to those in the siRNA-NC group. Downregulation of H19 decreased DVL2, cyclin D1, and ß-catenin expression and increased GSK-3ß expression. The inhibitory effects of downregulation of H19 on glioma cell proliferation, invasion, and migration were reversed by SKL2001 via the activation of the Wnt/ß-catenin signal pathway, which was further enhanced by inhibition of the Wnt/ß-catenin signal pathway by XAV939. CONCLUSIONS: H19 was overexpressed in glioma tissues and glioma cell lines. Downregulation of H19 inhibited cell proliferation, invasion, and migration, arrested cell cycle progression in the G0/G1 phase, and induced cell apoptosis by restraining activation of the Wnt/ß-catenin signaling pathway in glioma cells. Therefore, H19 is a potential therapeutic target for glioma therapy.

[Prevalence and related factors on diabetes among HIV/AIDS receiving antiretroviral therapy in Dehong Dai and Jingpo Autonomous Prefecture].

Objective: To study the prevalence and correlates of diabetes among HIV/AIDS who were on antiretroviral therapy (ART) in Dehong Dai and Jingpo autonomous prefectures (Dehong), Yunnan province. Methods: The database of HIV/AIDS receiving ART in Dehong was downloaded by using the basic information system of AIDS prevention and control in China. In this cross-sectional study, HIV/AIDS patients who were currently on ART and aged 18 years or above, were consecutively recruited, between July 2017 and June 2018, in Dehong. All the subjects underwent hemoglobin A1c (HbA1c) testing. Patient with diabetes was defined as meeting any of these indicators (HbA1c ≥6.5%, baseline FPG ≥7.0 mmol/L, FPG ≥7.0 mmol/L in the most recent visit). Both univariate and multivariate logistic regression analysis were carried on to evaluate the correlates of diabetes among the HIV/AIDS patients. Results: In total of 4 376 HIV/AIDS patients were included for analysis, with the average age as (43.7±10.1) years, proportion of males as 53.8% (2 356/4 376) and the HCV positive rate as 24.1% (1 055/4 376). The mean years was (8.9±3.8) years after the HIV diagnosis was made, and the mean duration on treatment was (6.8±2.9) years. The prevalence of diabetes was 11.4% (500/4 376). Through multivariate logistic regression analysis, data showed that the risk factors of diabetes of HIV/AIDS on ART were: aged 40 years or above, being male, HCV positive, baseline body mass index ≥24.0 kg/m(2), elevated TG ≥1.70 mmol/L in the most recent visit and baseline antiretroviral regimens under Efavirenz (EFV). Conclusions: Prevalence rate of diabetes appeared higher in HIV/AIDS patients who were on ART in Dehong. Prevention and control measures should be targeted on HIV/AIDS patients who were with risk factors of diabetes as being elderly, male, HCV positive, overweight and higher TG. Further esearch is needed to evaluate the association between the use of EFV and diabetes.

[Clinical implications and prognostic value of TP53 gene mutation and deletion in patients with myelodysplastic syndromes].

Objective: To explore the clinical implications and prognostic value of TP53 gene mutation and deletion in patients with myelodysplastic syndromes (MDS) . Methods: 112-gene targeted sequencing and interphase fluorescence in situ hybridization (FISH) were used to detect TP53 mutation and deletion in 584 patients with newly diagnosed primary MDS who were admitted from October 2009 to December 2017. The association of TP53 mutation and deletion with several clinical features and their prognostic significance were analyzed. Results: Alterations in TP53 were found in 42 (7.2%) cases. Of these, 31 (5.3%) cases showed TP53 mutation only, 8 (1.4%) cases in TP53 deletion only, 3 (0.5%) cases harboring both mutation and deletion. A total of 37 mutations were detected in 34 patients, most of them (94.6%) were located in the DNA binding domain (exon5-8) , the remaining 2 were located in exon 10 and splice site respectively. Patients with TP53 alterations harbored significantly more mutations than whom without alterations (z=-2.418, P=0.016) . The median age of patients with TP53 alterations was higher than their counterparts[60 (21-78) years old vs 52 (14-83) years old, z=-2.188, P=0.029]. TP53 alterations correlated with complex karyotype and International prognostic scoring system intermediate-2/high significantly (P<0.001) . Median overall survival of patients with TP53 alterations was shorter than the others[13 (95%CI 7.57-18.43) months vs not reached, χ(2)=12.342, P<0.001], while the significance was lost during complex karyotype adjusted analysis in multivariable model. Conclusion: TP53 mutation was more common than deletion in MDS patients. The majority of mutations were located in the DNA binding domain. TP53 alterations were strongly associated with complex karyotype and always coexisted with other gene mutations. TP53 alteration was no longer an independent prognostic factor when complex karyotype were occurred in MDS.

[A study of clinical characteristics and prognosis of primary myelofibrosis patients with thrombocytopenia in varied degrees].

Objective: To evaluate clinical characteristics and prognosis of primary myelofibrosis (PMF) patients with thrombocytopenia in varied degrees. Methods: Clinical features and survival data of 1 305 Chinese patients with PMF were retrospectively analyzed. The prognostic value of thrombocytopenia in patients with PMF was evaluated. Results: 320 subjects (47%) presented severe thrombocytopenia (PLT<50×10(9)/L), 198 ones (15.2%) mild thrombocytopenia [PLT (50-99)×10(9)/L] and 787 ones (60.3%) without thrombocytopenia (PLT ≥ 100×10(9)/L). The more severe the thrombocytopenia, the higher the proportions of HGB<100 g/L, WBC<4×10(9)/L, circulating blasts ≥ 3%, abnormal karyotype and unfavourable cytogenetics (P<0.001, P<0.001, P=0.004, P<0.001 and P<0.001, respectively) were observed in this cohort of patients. The more severe the thrombocytopenia, the lower the proportion of JAK2V617F positive (P<0.001) was also noticed. Platelet count was positively correlated with splenomegaly, HGB and WBC (P<0.001, correlation coefficients were 0.131, 0.445 and 0.156, respectively). Platelet count was negative correlated with constitutional symptoms and circulating blasts (P=0.009, P=0.045, respectively; correlation coefficients were -0.096 and -0.056, respectively). The median survival of patients with severe thrombocytopenia, mild thrombocytopenia and without thrombocytopenia were 32, 67 and 89 months, respectively (P<0.001). Multivariate analysis identified thrombocytopenia in varied degrees (HR=1.693, 95%CI 1.320-2.173, P<0.001) and Dynamic Internation Prognostic Scoring System(DIPSS) prognostic model (HR=2.051, 95%CI 1.511-2.784, P<0.001) as independent risk factors for survival. Conclusion: PMF patients with severe thrombocytopenia frequently displayed anemia, leucopenia, circulating blasts and short survival, so active treatment measures should be taken especially in these patients.

Differentiation of focal organising pneumonia and peripheral adenocarcinoma in solid lung lesions using thin-section CT-based radiomics.

AIM: To evaluate the predictive role of radiomics based on computed tomography (CT) in discriminating focal organising pneumonia (FOP) from peripheral lung adenocarcinoma (LA). MATERIALS AND METHODS: Institutional research board approval was obtained for this retrospective study. One hundred and seventeen patients with FOP and 109 patients with LA who underwent thin-section CT from January 2011 to August 2017 were reviewed systematically and analysed. The clinical and radiological features were established as model A and multi-feature-based radiomics as model B. The diagnostic performance of model A, model B, and model A+B were evaluated and compared via receiver operating characteristic (ROC) curve analysis and logistic regression analysis. RESULTS: Sex, symptoms, necrosis, and the halo sign were identified as independent predictors of LA. The area under the ROC curve (Az value), accuracy, sensitivity, and specificity of model A were 0.839, 75.7%, 82.6%, and 69.2% respectively. Model B showed significantly higher accuracy than model A (83.6% versus 75.7%, p=0.032). The top four best-performing features, WavEnLH_s-3, WavEnHH_s-3, Teta3, and Volume, performed as independent factors for discriminating LA. Regression analysis indicated that model B had superior model fit than model A with Akaike information criterion (AIC) values of 73.6% versus 59.1%, respectively. Combining model A with model B is useful in achieving better diagnostic performance in discriminating FOP from LA: the Az value, accuracy, sensitivity, and specificity were 0.956, 87.6%, 85.3%, and 89.7% respectively. CONCLUSIONS: Radiomics based on CT exhibited better diagnostic accuracy and model fit than clinical and radiological features in discriminating FOP from LA. Combination of both achieved better diagnostic performance.