Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1­G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1­G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7­G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9­G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.

Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial).

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

Study on the Application of Concentrated Growth Factor Combined With Adipose Transplantation in Repairing Depressed Deformities of Soft Tissue in the Face.

BACKGROUND: Autologous fat is a rich source of adipose tissue that is safe for transplantation. Decreasing the long-term absorption rate is key to improve the survival of transplanted adipose tissue. The aim of this study was to assess the effect of concentrated growth factor (CGF) on the survival of transplanted adipose tissue for repair of facial depression malformations. METHODS: Coleman adipose granules (CAGs) were prepared from venous blood. In the animal experiment, the ears of 30 healthy male New Zealand white rabbits were randomly allocated to 1 of 4 groups: CGF + CAG (CGF group), platelet-rich fibrin (PRF) + CAG (PRF group), CAG alone (CAG group), and adipose granule transplantation group (control group). Postoperative survival of the transplanted adipose tissue was assessed, the survival and absorption rates of adipose were calculated, and immunohistochemical analysis of specimens was conducted by staining with hematoxylin and eosin and Oil Red O. Of 43 outpatients, 22 received simple adipose transplantation and 21 received autologous CGF combined with adipose transplantation. The adipose absorption rate, complication rate, and cosmetic improvement of the 2 groups were compared. RESULTS: More adipocytes that are normal were observed in the CGF group, with fewer vacuoles and more uniform distribution of adipose tissue. Survival of the adipose tissue was superior in the CGF and PRF groups. Meanwhile, vascular density and long-term stability were better in the CGF group than the PRF group. In terms of clinical efficacy, the uniformity and survival rate of the adipose tissue were relatively improved in the CGF group compared with the simple adipose particle transplantation group, with less early liquefaction. CONCLUSION: Concentrated growth factor stabilized and improved the survival of transplanted adipose tissue for filling of facial depression malformations.

CDKN2A deletions are associated with poor outcomes in 101 adults with T-cell acute lymphoblastic leukemia.

The identification of genetic risk subgroups of T-cell acute lymphoblastic leukemia (T-ALL) may provide evidence for risk stratification and individualized treatment. We investigated the characteristics and prognostic value of tumor suppressor gene CDKN2A deletions in 101 patients with T-ALL. The CDKN2A deletion was present in 23% (23/101) of T-ALL by fluorescence in situ hybridization (FISH). The most common type of CDKN2A deletion was homozygous deletion (70%, 16/23). A lower frequency of CDKN2A deletion was found in patients with early T-cell precursor (ETP) ALL than in patients with non-ETP-ALL (10.4% vs 34.0%; P = .008). Deletion of CDKN2A was significantly associated with younger age (P = .001), higher white blood cell (WBC) count (P < .001) and higher lactate dehydrogenase (LDH) level (P = .002). Patients with CDKN2A deletion had lower 2-year overall survival (OS) and event-free survival (EFS) rates than patients without CDKN2A deletion (2-year OS: 18.6% ± 8.9% vs 47.4% ± 6.2%, P = .032; EFS: 16.4 ± 8.3 vs 38.6 ± 5.9%, P = .022). In multivariable analysis, CDKN2A deletion was an independent adverse prognostic factor for OS (P = .016). In conclusion, adult T-ALL patients with CDKN2A deletion had a poor prognosis, and these patients might benefit from intensive chemotherapy or allogeneic hematopoietic stem-cell transplantation.

Chd7 Is Critical for Early T-Cell Development and Thymus Organogenesis in Zebrafish.

Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome is a congenital disorder affecting multiple organs and mainly caused by mutations in CHD7, a gene encoding a chromatin-remodeling protein. Immunodeficiency and reduced T cells have been noted in CHARGE syndrome. However, the mechanisms underlying T lymphopenia are largely unexplored. Herein, we observed dramatic decrease of T cells in both chd7knockdown and knockout zebrafish embryos. Unexpectedly, hematopoietic stem and progenitor cells and, particularly, lymphoid progenitor cells were increased peripherally in nonthymic areas in chd7-deficient embryos, unlikely to contribute to the T-cell decrease. Further analysis demonstrated that both the organogenesis and homing function of the thymus were seriously impaired. Chd7 might regulate thymus organogenesis through modulating the development of both neural crest cell-derived mesenchyme and pharyngeal endoderm-derived thymic epithelial cells. The expression of foxn1, a central regulator of thymic epithelium, was remarkably down-regulated in the pharyngeal region in chd7-deficient embryos. Moreover, the T-cell reduction in chd7-deficient embryos was partially rescued by overexpressing foxn1, suggesting that restoring thymic epithelium may be a potential therapeutic strategy for treating immunodeficiency in CHARGE syndrome. Collectively, the results indicated that chd7 was critical for thymic development and T-lymphopenia in CHARGE syndrome may be mainly attributed to the defects of thymic organogenesis. The current finding may benefit the diagnosis and therapy of T lymphopenia and immunodeficiency in CHARGE syndrome.

Utility of CT assessment in hematology patients with invasive aspergillosis: a post-hoc analysis of phase 3 data.

BACKGROUND: Pulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive fungal diseases like invasive aspergillosis, and may identify radiographic abnormalities, such as halo signs or air-crescent signs. We assessed the diagnostic utility of CT assessment in patients with hematologic malignancies or those who had undergone allogeneic hematopoietic stem cell transplantation in whom invasive aspergillosis was suspected. METHODS: This post-hoc analysis assessed data from a prospective, multicenter, international trial of voriconazole (with and without anidulafungin) in patients with suspected invasive aspergillosis (IA; proven, probable, or possible, using 2008 European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria) [NCT00531479]. Eligible patients received at least one baseline lung CT scan. RESULTS: Of 395 patients included in this post-hoc analysis, 240 patients (60.8%) had 'confirmed' proven (9/240, 3.8%) or probable (231/240, 96.3%) invasive aspergillosis (cIA) and 155 patients (39.2%) had 'non-confirmed' invasive aspergillosis (all nIA; all possible IA (de Pauw et al., Clin Infect Dis 46:1813-21, 2008)). Mean age was 52.3 and 50.5 years, 56.3 and 60.0% of patients were male, and most patients were white (71.7 and 71.0%) in the cIA and nIA populations, respectively. Median baseline galactomannan was 1.4 (cIA) and 0.2 (nIA), mean Karnofsky score was 65.3 (cIA) and 66.8 (nIA), and mean baseline platelet count was 48.0 (cIA) and 314.1 (nIA). Pulmonary nodules (46.8% of all patients), bilateral lung lesions (37.5%), unilateral lung lesions (28.4%), and consolidation (24.8%) were the most common radiographic abnormalities. Ground-glass attenuation (cIA: 24.2%; nIA: 11.6%; P < 0.01) and pulmonary nodules (cIA: 52.5%; nIA: 38.1%; P < 0.01) were associated with cIA. Other chest CT scan abnormalities (including halo signs and air-crescent signs) at baseline in patients with hematologic malignancy or hematopoietic stem cell transplantation, and suspected IA, were not associated with cIA. CONCLUSIONS: These findings highlight the limitations in the sensitivity of chest CT scans for the diagnosis of IA, and reinforce the importance of incorporating other available clinical data to guide management decisions on individual patients, including whether empirical treatment is reasonable, pending full evaluation. TRIAL REGISTRATION: NCT00531479 (First posted on ClinicalTrials.gov on September 18, 2007).

Propranolol Accelerats Hemangioma Stem Cell Transformation Into Adipocyte.

BACKGROUND: Infantile hemangioma (IH) is the most common childhood benign vascular tumor. Recently, propranolol has been found to be an effective therapy for IH, but its mechanism of action is not yet understood. Hemangioma stem cells (HemSCs) have a mesenchymal morphology, robust proliferation, and multilineage differentiation (into adipocytes). Therefore, we hypothesized that propranolol could accelerate the transdifferentiation of HemSCs and prevent the growth of proliferating IH. In this study, the fibrofatty tissue of IH that received therapy with propranolol appeared much earlier than without the treatment. METHODS: We isolated HemSCs with CD133-tagged immunomagnetic beads, and then we used flow cytometry technology to analyze the HemSC phenotypes and determine whether propranolol induced HemSC death. The proliferation and adipogenesis abilities of propranolol-treated HemSCs were analyzed by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide assay, Oil red O staining, and Western blotting. RESULTS: We observed that the HemSC morphological traits gradually became spindle shaped, like fibroblasts, and the average extraction yield of HemSCs was about 0.25%. The HemSCs had high rates of expression for CD90 (98.8%) and CD105 (97.8%) but did not significantly express CD31 (0.7%). We also found a 100 µM concentration of propranolol cutoff point. Propranolol did not affect HemSC survival significantly at low concentrations (6.25, 12.5, 25.0, and 50.0 µM). However, propranolol resulted in a sharp and significant variation in cell morphology and survival rates at high concentrations (100, 200, and 400 µM). The results suggest that treatment with propranolol inhibited HemSC proliferation and induced cell death and apoptosis in a concentration-dependent manner. Oil droplets determined by Oil red O staining showed that propranolol increased the transdifferentiation rate of HemSCs into adipocytes. Furthermore, the expressions of phosphorylated AKT and peroxisome proliferator-activated receptor gamma (PPARγ) were increased with a 100 µM concentration of propranolol in HemSC culture. CONCLUSIONS: Our study found that propranolol inhibited proliferation, induced apoptosis and necrosis, and promoted differentiation of HemSCs. Propranolol may upregulate PPARγ via PI3K pathways, thereby accelerating lipogenesis and enhancing IH HemSC adipogenesis.

P53 codon 72 polymorphism, human papillomavirus infection, and their interaction to oral carcinoma susceptibility.

BACKGROUND: Tumor suppressor gene p53 plays an important role in the maintenance of the genomic integrity, and mutation in the gene may alter an individual's susceptibility to various carcinomas. P53 Arg72Pro or codon 72 polymorphism has been indicated to increase the risk of developing certain cancers such as bladder cancer and cervical cancer. Human papillomavirus (HPV) infection has been shown as a risk factor for certain cancers such as cervical cancer and oral cancer as well, and the HPV oncoprotein E6 may induce the degradation of p53 function. However, the association between p53 Arg72Pro polymorphism and the risk of oral cancer with HPV infection remains inconclusive. Therefore, this meta-analysis involving 5,614 participants was performed to investigate the relations among the p53 Arg72Pro polymorphism, HPV infection, and the risk of developing oral cancer. RESULTS: A search of the literature by PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases was conducted to identify studies based on the inclusion and exclusion criteria. Odds ratios with 95% confidence intervals were combined using a random-effect model or a fixed-effect model. The current study was conducted with 13 studies consisting of 2,413 cases and 3,201 controls. Neither overall analysis nor stratified analyses detected any obvious evidence of association between p53 Arg72Pro polymorphism and oral cancer susceptibility in all genetic models. However, a significant association between p53 Arg72Pro polymorphism and the risk of oral cancer with HPV infection was detected in the Arg/Arg vs. Arg/Pro + Pro/Pro model. CONCLUSION: In the current meta-analysis which used the quantitative data synthesis for the first time, our study demonstrated that p53 Arg72Pro polymorphism together with HPV infection might jointly alter an individual's susceptibility to the risk of oral cancer. Our results suggested that p53 Arg72Pro polymorphism may partly contribute to the pathogenesis of oral cancer development.

The effectiveness of propranolol in treating infantile haemangiomas: a meta-analysis including 35 studies.

AIMS: Propranolol may have shown excellent results as a first line therapy in infantile haemangiomas (IHs) at all sites in the body, but this conclusion remains controversial. In an attempt to resolve this issue, we performed a meta-analysis. METHODS: A search of the literature using PubMed, MEDLINE, Cochrane Library databases and China National Knowledge Infrastructure (CNKI) was performed to identify studies which estimated the efficacy of propranolol therapy in infants with haemangiomas all sites of the body. The pooled odds ratio (OR) along with the corresponding 95% confidence intervals (CI) were assessed using a fixed effects model. RESULTS: Thirty-five studies involving 324 infantile haemangioma(IH) patients and 248 controls were retrieved and analyzed. The efficacy of propranolol was greater than other therapies in treating IHs (OR = 9.67, 95% CI 6.62, 14.12, P < 0.001). In a stratified analysis by sites of tumour, propranolol was a more effective therapy when compared with steroids (OR = 9.67, 95% CI 6.61, 14.15, P < 0.001), vincristine (OR = 9.00, 95% CI 2.15, 37.66, P = 0.003) and laser treatment (OR = 9.00, 95% CI 1.42, 57.12, P = 0.020) in treating cutaneous IHs (OR = 24.95, 95% CI 9.48, 65.64, P < 0.001), peri-ocular IHs (OR = 9.39, 95% CI 3.88, 22.71, P < 0.001), infantile airway haemangiomas (OR = 20.91, 95% CI 7.81, 55.96, P < 0.001) and infantile hepatic haemangiomas (OR = 9.89, 95% CI 1.20, 81.54, P = 0.033). CONCLUSION: The current meta-analysis provided strong evidence for propranolol as a first line therapy for IHs.

Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial.

BACKGROUND: Homoharringtonine-based induction regimens have been widely used in China for patients with acute myeloid leukaemia. However, their efficacy has not been tested in a multicentre randomised controlled trial in a large population. We assessed the efficacy and safety of homoharringtonine-based induction treatment for management of newly diagnosed acute myeloid leukaemia. METHODS: This open-label, randomised, controlled, phase 3 study was done in 17 institutions in China between September, 2007, and July, 2011. Untreated patients aged 14-59 years with acute myeloid leukaemia were randomly assigned (by a computer-generated allocation schedule without stratification) to receive one of three induction regimens in a 1:1:1 ratio: homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and aclarubicin 20 mg/day on days 1-7 (HAA); homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and daunorubicin 40 mg/m(2) per day on days 1-3 (HAD); or daunorubicin 40-45 mg/m(2) per day on days 1-3 and cytarabine 100 mg/m(2) per day on days 1-7 (DA). Patients in complete remission were offered two cycles of intermediate-dose cytarabine (2 g/m(2) every 12 h on days 1-3). The primary endpoints were the proportion of patients who achieved complete remission after two cycles of induction treatment and event-free survival in the intention-to-treat population. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-TRC-06000054. FINDINGS: We enrolled 620 patients, of whom 609 were included in the intention-to-treat analysis. 150 of 206 patients (73%) in the HAA group achieved complete remission versus 125 of 205 (61%) in the DA group (p=0.0108); 3-year event-free survival was 35.4% (95% CI 28.6-42.2) versus 23.1% (95% CI 17.4-29.3; p=0.0023). 133 of 198 patients (67%) in the HAD group had complete remission (vs DA, p=0·20) and 3-year event-free survival was 32.7% (95% CI 26.1-39.5; vs DA, p=0.08). Adverse events were much the same in all groups, except that more patients in the HAA (12 of 206 [5.8%]) and HAD (13 of 198 [6.6%]) groups died within 30 days than in the DA group (two of 205 [1%]; p=0.0067 vs HAA; p=0.0030 vs HAD). INTERPRETATION: A regimen of homoharringtonine, cytarabine, and aclarubicin is a treatment option for young, newly diagnosed patients with acute myeloid leukaemia. FUNDING: Chinese National High Tech Programme, Key Special Research Foundation of the Ministry of Science and Technology of China, National Nature Science Foundation of China, National Clinical Key Specialty Construction Project.

Plexin B3 guides axons to cross the midline in vivo.

During the development of neural circuits, axons are guided by a variety of molecular cues to navigate through the brain and establish precise connections with correct partners at the right time and place. Many axon guidance cues have been identified and they play pleiotropic roles in not only axon guidance but also axon fasciculation, axon pruning, and synaptogenesis as well as cell migration, angiogenesis, and bone formation. In search of receptors for Sema3E in axon guidance, we unexpectedly found that Plexin B3 is highly expressed in retinal ganglion cells of zebrafish embryos when retinal axons are crossing the midline to form the chiasm. Plexin B3 has been characterized to be related to neurodevelopmental disorders. However, the investigation of its pathological mechanisms is hampered by the lack of appropriate animal model. We provide evidence that Plexin B3 is critical for axon guidance in vivo. Plexin B3 might function as a receptor for Sema3E while Neuropilin1 could be a co-receptor. The intracellular domain of Plexin B3 is required for Semaphorin signaling transduction. Our data suggest that zebrafish could be an ideal animal model for investigating the role and mechanisms of Sema3E and Plexin B3 in vivo.

3-Hydroxy-3-methylglutaryl coenzyme A reductase genes from Glycine max regulate plant growth and isoprenoid biosynthesis.

Isoprenoids, a large kind of plant natural products, are synthesized by the mevalonate (MVA) pathway in the cytoplasm and the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway in plastids. As one of the rate-limiting enzymes in the MVA pathway of soybean (Glycine max), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is encoded by eight isogenes (GmHMGR1-GmHMGR8). To begin, we used lovastatin (LOV), a specific inhibitor of GmHMGR, to investigate their role in soybean development. To further investigate, we overexpressed the GmHMGR4 and GmHMGR6 genes in Arabidopsis thaliana. The growth of soybean seedlings, especially the development of lateral roots, was inhibited after LOV treatment, accompanied by a decrease in sterols content and GmHMGR gene expression. After the overexpression of GmHMGR4 and GmHMGR6 in A. thaliana, the primary root length was higher than the wild type, and total sterol and squalene contents were significantly increased. In addition, we detected a significant increase in the product tocopherol from the MEP pathway. These results further support the fact that GmHMGR1-GmHMGR8 play a key role in soybean development and isoprenoid biosynthesis.

Nucleus accumbens D1/D2 circuits control opioid withdrawal symptoms in mice.

The nucleus accumbens (NAc) is the most promising target for drug use disorder treatment. Deep brain stimulation (DBS) of NAc is effective for drug use disorder treatment. However, the mechanisms by which DBS produces its therapeutic effects remain enigmatic. Here, we define a behavioral cutoff criterion to distinguish depressive-like behaviors and non-depressive-like behaviors in mice after morphine withdrawal. We identified a basolateral amygdala (BLA) to NAc D1 medium spiny neuron (MSN) pathway that controls depressive-like behaviors after morphine withdrawal. Furthermore, the paraventricular nucleus of thalamus (PVT) to NAc D2 MSN pathway controls naloxone-induced acute withdrawal symptoms. Optogenetically induced long-term potentiation with κ-opioid receptor (KOR) antagonism enhanced BLA to NAc D1 MSN signaling and also altered the excitation/inhibition balance of NAc D2 MSN signaling. We also verified that a new 50 Hz DBS protocol reversed morphine withdrawal-evoked abnormal plasticity in NAc. Importantly, this refined DBS treatment effectively alleviated naloxone-induced withdrawal symptoms and depressive-like behaviors and prevented stress-induced reinstatement. Taken together, the results demonstrated that input- and cell type-specific synaptic plasticity underlies morphine withdrawal, which may lead to novel targets for the treatment of opioid use disorder.

Mediating Effects of Adolescent Physical Activity, Self-Rated Health and Family Income.

Objective: To investigate and analyse the situation and relationship between adolescent physical activity and self-assessment of health to provide a reference for adolescent physical activity research. Methods: A questionnaire was used to investigate the physical activity and self-rated health of 1,804 adolescents aged 14-18 years. Results: There was a significant relationship between adolescents' physical activity and self-rated health. The coefficient was 0.109 (P < 0.01) in urban areas and 0.127 (P < 0.01) in rural areas. At the same time, it was found that when family income was used as the intermediary variable between physical activity and self-rated health, the intermediary effect was 0.12 (P < 0.01), and the intermediary effect accounted for 25.97%. Conclusion: Adolescent obesity, physical activity, smoking, wellbeing and physical activity can affect adolescents' self-rated health status. At the same time, it is also found that adolescents' family income is an intermediary variable between physical activity and self-rated health. Suggestions: (1) Increase the methods of sports venues, sports organizations and sports activities, improve the possibility of teenagers participating in physical activities, and improve teenagers' self-rated health; (2) There is a large gap between the physical activity and self-rated health of urban and rural adolescents. Increasing the guidance of physical activity of adolescents in rural areas promotes the balance of self-rated health of urban and rural adolescents. (3) Family income is the intermediary variable of teenagers' physical activities and self-rated health. Reducing family expenditure through financial transfer payments or reducing taxes and fees can increase the level of teenagers' physical and mental health.

Oral arsenic and retinoic acid for high-risk acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) has become curable over 95% patients under a complete chemo-free treatment with all-trans retinoic acid (ATRA) and arsenic trioxide in low-risk patients. Minimizing chemotherapy has proven feasible in high-risk patients. We evaluated oral arsenic and ATRA without chemotherapy as an outpatient consolidation therapy and no maintenance for high-risk APL. We conducted a multicenter, single-arm, phase 2 study with consolidation phases. The consolidation therapy included Realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen for 4 cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary end point was the disease-free survival (DFS). Secondary end points included measurable resident disease, overall survival (OS), and safety. A total of 54 participants were enrolled at seven centers from May 2019. The median age was 40 years. At the median follow-up of 13.8 months (through April 2022), estimated 2-year DFS and OS were 94% and 100% in an intention-to-treat analysis. All the patients achieved complete molecular remission at the end of consolidation phase. Two patients relapsed after consolidation with a cumulative incidence of relapse of 6.2%. The majority of adverse events were grade 1-2, and only three grade 3 adverse events were observed. Oral arsenic plus ATRA without chemotherapy was active as a first-line consolidation therapy for high-risk APL.Trial registration: chictr.org.cn number, ChiCTR1900023309.

Short-term efficacy and safety of a lower dose of polyethylene glycol recombinant human growth hormone in children with growth hormone deficiency: A randomized, dose-comparison study.

Objective: Polyethylene glycol recombinant human growth hormone (PEG-rhGH, Jintrolong®) is the first long-acting rhGH preparation that is approved to treat children with growth hormone deficiency (GHD) in China. Clinical experience with dose selections of PEG-rhGH is scarce. The present study compared the efficacy and safety of a lower dose to increase dosing regimens of PEG-rhGH treatment. Methods: A multicenter, randomized, open-label, dose-comparison clinical study was conducted to compare the improvements in the height standard deviation score (Ht SDS), height velocity (HV), insulin-like growth factor-1 (IGF-1) SDS, and safety profiles of children with GHD who are treated with 0.2 mg/kg/week of PEG-rhGH dose or 0.14 mg/kg/week for 26 weeks. Results: Ht SDS, HV, and IGF-1 SDS increased significantly after PEG-rhGH treatment in the two dose groups (p < 0.05). The improvements of Ht SDS, HV, and IGF-1 SDS were more significant in the high-dose group than in the low-dose group (p < 0.05). Ht SDS improvement in low-dose group was not non-inferiority to that in the high-dose group (p = 0.2987). The incidences of adverse events were comparable between the two groups. Conclusion: The improvements of Ht SDS, HV, and IGF-1 SDS were more significant in the high-dose group than in the low-dose group (p < 0.05). PEG-rhGH at the dose of 0.14 mg/kg/week was effective and safe for children with GHD. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02908958.

Screening and Identification of Key Biomarkers in Melanoma: Evidence from Bioinformatic Analyses.

Melanoma is an extremely malignant and occult tumor. To identify candidate genes related to melanoma carcinogenesis and progression, the microarray data sets GSE83583, GSE130244, and GSE31879 were retrieved from the Gene Expression Omnibus (GEO) database using the GEO2R analytical tool provided by the National Center for Biotechnology Information (NCBI). Gene expression analysis was carried out using the DAVID database for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses of differentially expressed genes. A protein-protein interaction network was constructed with the STRING database, the interaction data were imported into Cytoscape software, and the network topology was analyzed to identify key genes. Hub gene expression was verified in the Gene Expression Profiling Interactive Analysis and Human Protein Atlas databases. In addition, Kaplan-Meier survival analysis was performed on hub genes. A total of 142 differentially expressed genes were identified in melanoma tissues, including 50 upregulated genes and 92 downregulated genes. Five central genes (CCNA2, EBP, GABBR2, TRIM32, and ADAM10) were found based on the degree of the nodes. These genes are mainly enriched in protein serine/threonine kinase activity and apoptosis pathways. Survival analysis showed CCNA2 to be related to the overall survival (OS) of patients, and increased expression of TRIM32 led to increased OS and disease-free survival risk. Bioinformatics methods can be used to effectively select key genes in melanoma, and CCNA2 and TRIM32 may be new targets for treatment of this disease.

Artificial Dermis and Autologous Platelet-Rich Plasma for Treatment of Refractory Wounds: A Clinical Study.

Refractory wounds present a complex and serious clinical dilemma in plastic and reconstructive surgery. However, there are currently no standard guidelines for the treatment of refractory wounds. Artificial dermis (AD) has achieved some satisfactory results, but also has some limitations. Autologous platelet-rich plasma (PRP), as a cell-therapy material, was a valuable and safe treatment dressing for chronic non-healing wounds. This study aimed to evaluate the efficacies of artificial dermis (AD) with and without autologous platelet-rich plasma (PRP) in patients with refractory wounds. Sixteen patients with refractory wounds were randomly allocated to autologous PRP therapy combined with artificial dermis (PRP + AD [N = 8]) or an artificial dermis program only (AD [N = 8]). We compared the efficacies of the two methods in terms of times to wound healing, infection control, and AD vascularization, as well as hospitalization days and eventual clinical outcomes.13 patients achieved complete healing, including seven (87.5%) in the PRP + AD group and six (75.0%) in the AD group (P > .05). The times to wound healing, infection control, and AD vascularization, and hospitalization time after transfer were significantly shorter in the PRP + AD group compared with the AD group (P < .05). In conclusion, the combination of AD and PRP promoted refractory wound healing and shortened waiting times compared with simple dermal grafts.

miR­139­5p affects cell proliferation, migration and adipogenesis by targeting insulin­like growth factor 1 receptor in hemangioma stem cells.

Infant hemangioma is the most common benign tumor in infancy. The pathological development process of this tumor is separated into the proliferation period, the involution period and the composite period in which a few residual capillary­like vessels grow through the loose fibrofatty tissue. Previous studies have confirmed that insulin­like growth factor 1 (IGF­1) is able to facilitate the cell proliferation of hemangioma stem cells (HemSCs) and the differentiation of HemSCs into adipocytes. Additionally, studies have confirmed that microRNAs (miRs) may serve a crucial function in regulating the IGF­1 receptor (IGF­1R). miR­139­5p often functions as a tumor suppressor. The present study was designed to investigate the mechanism of miR­139­5p in HemSCs. Dual luciferase reporter results verified that IGF­1R is the target gene of miR­139­5p. miR­139­5p overexpression reduced IGF­1R expression, and miR­139­5p inhibition increased IGF­1R expression. Cell Counting Kit­8 and Transwell migration assays demonstrated that miR­139­5p overexpression may target IGF­1R to inhibit the proliferation in addition to the migration of HemSCs. Reverse transcription­quantitative PCR, oil red o staining and western blot analysis confirmed that miR­139­5p overexpression was able to reduce adipogenesis in HemSCs via the IGF­1/IGF­1R pathway. In contrary, miR­139­5p inhibition substantially enhanced the proliferation, migration and adipogenesis of HemSCs. Overall, miR­139­5p is able to affect the IGF­1/IGF­1R pathway by regulating IGF­1R expression, which ultimately affects the proliferation, migration and adipogenesis of HemSCs.