Intensive chemotherapy with dual induction and ALL-like consolidation for childhood acute myeloid leukemia: a respective report from multiple centers in China.

Background: Pediatric acute myeloid leukemia (AML) has poor prognosis and high rate of relapse and mortality, and exploration of new treatment options is still critically needed. Objectives: To summarize the outcome of our new treatment strategies for pediatric AML, which is characterized by dual induction and acute lymphoblastic leukemia (ALL) elements consolidation. Design: Retrospective, single-arm study. Methods: From July 2012 to December 2019, an intensive chemotherapy protocol was used for newly diagnosed children with AML, which contains dual induction, three courses of consolidations based on high-dose cytarabine, and two courses of consolidations composed of high-dose methotrexate, vincristine, asparaginase, and mercaptopurine (ALL-like elements). Blasts were monitored by bone marrow smears at intervals, and two lumbar punctures were performed during chemotherapy. We retrospectively analyzed the efficacy and safety of this study. The last follow-up was on 26 May 2023. Results: A total of 70 pediatric AMLs were included. The median age at diagnosis was 6.7 (0.5-16.0) years. The median initial WBC count was 23.74 × 109/L, 11 of whom ⩾100 × 109/L. After dual induction, there were 62 cases of complete remission (CR), 5 cases of partial remission, and 3 cases of nonremission. The CR rate was 88.57%. The median follow-up time was 5.8 (0.2-9.4) years, the 5-year overall survival was 78.2% ± 5%, the event-free survival (EFS) was 71.2% ± 5.6%, and the cumulative recurrence rate was 27.75%. The 5-year EFS of patients with initial WBC < 100 × 109/L (n = 59) and ⩾100 × 109/L (n = 11) were 76.4% ± 5.7% and 45.5% ± 15% (p = 0.013), respectively. A total of 650 hospital infections occurred. The main causes of infection were respiratory tract infection (26.92%), septicemia (18.46%), stomatitis (11.85%), and skin and soft-tissue infection (10.46%). Conclusion: This intensive treatment protocol with dual induction and ALL-like elements is effective and safe for childhood AML. Initial WBC ⩾ 100 × 109/L was the only independent risk factor in this cohort. Trial registration: It is a retrospective study, and no registration on ClinicalTrials.gov.

Outcomes of a novel all-inside arthroscopic anterior talofibular ligament repair for chronic ankle instability.

PURPOSE: This study aimed to introduce a novel all-inside arthroscopic anterior talofibular ligament (ATFL) repair for chronic ankle instability (CAI) with a knotless suture anchor technique-Hugging Repair, evaluate clinical outcomes, and analyze the associated risk factors. METHODS: A total of 84 patients (42 males and 42 females, mean age: 36.1 ± 11.2 years, range: 19-68 years) who underwent Hugging Repair from January 1, 2016 to December 31, 2018, were enrolled in this retrospective study. The American Orthopedic Foot and Ankle Society (AOFAS) score, Karlsson Ankle Functional Score (KAFS), Foot and Ankle Outcome Score (FAOS), Tegner score, and Numerical Rating Scale (NRS) were evaluated pre-operatively and at final follow-up. The potential risk factors such as age, body mass index (BMI), sex, post-injury duration (time from injury to surgery), follow-up time, number of anchors, concomitant injuries [e.g., osteochondral defects (OCD), sinus tarsi syndrome (STS), anterior ankle impingement (AAI)], first-time treatment, and number of ankle sprains were also analyzed through multiple regression analysis. RESULTS: There were 68 (81%) patients followed up for a mean time of 42 (range: 35-50) months. The median AOFAS score increased from 65 (35-72) to 90 (77-100), KAFS increased from 64 (38-71) to 90 (62-100), FAOS increased from 68 (50-70) to 97 (68-100), Tegner score increased from 1 (1-3) to 4 (2-7), and NRS increased from 3.5 (2-5) to 1 (0-3). No correlation was found between the functional scores and risk factors mentioned above. In the multivariate model, age was significantly negatively associated with KAFS, FAOS, and Tegner activity scale (P = 0.013; P = 0.002; P = 0.000); female was significantly associated with poorer Tegner activity scale (P = 0.004); and the presence of concomitant injuries was significantly negatively associated with AOFAS score (P = 0.033). CONCLUSION: The novel all-inside arthroscopic ATFL repair for CAI with a knotless suture anchor technique-Hugging Repair is a safe and suitable technique that achieves satisfactory clinical outcomes and provides an effective option for the treatment of CAI. Risk factors for patients who underwent all-inside ATFL repair were older age, female sex, and concomitant injuries.

Prognostic significance of CNSL at diagnosis of childhood B-cell acute lymphoblastic leukemia: A report from the South China Children's Leukemia Group.

Objectives: The prognostic significance of acute lymphoblastic leukemia (ALL) patients with central nervous system leukemia (CNSL) at diagnosis is controversial. We aimed to determine the impact of CNSL at diagnosis on the clinical outcomes of childhood B-cell ALL in the South China Children's Leukemia Group (SCCLG). Methods: A total of 1,872 childhood patients were recruited for the study between October 2016 and July 2021. The diagnosis of CNSL depends on primary cytological examination of cerebrospinal fluid, clinical manifestations, and imaging manifestations. Patients with CNSL at diagnosis received two additional courses of intrathecal triple injections during induction. Results: The frequency of CNLS at the diagnosis of B-cell ALL was 3.6%. Patients with CNSL at diagnosis had a significantly higher mean presenting leukocyte count (P = 0.002) and poorer treatment response (P <0.05) compared with non-CNSL patients. Moreover, CNSL status was associated with worse 3-year event-free survival (P = 0.030) and a higher risk of 3-year cumulative incidence of relapse (P = 0.008), while no impact was observed on 3-year overall survival (P = 0.837). Multivariate analysis revealed that CNSL status at diagnosis was an independent predictor with a higher cumulative incidence of relapse (hazard ratio = 2.809, P = 0.016). Conclusion: CNSL status remains an adverse prognostic factor in childhood B-cell ALL, indicating that additional augmentation of CNS-directed therapy is warranted for patients with CNSL at diagnosis.

A lineage-specific arginine in POS1 is required for fruit size control in Physaleae (Solanaceae) via gene co-option.

Solanaceae have important economic value mainly due to their edible fruits. Physalis organ size 1/cytokinin response factor 3 (POS1/CRF3), a unique gene in Solanaceae, is involved in fruit size variation in Physalis but not in Solanum. However, the underlying mechanisms remain elusive. Here, we found that POS1/CRF3 was likely created via the fusion of CRF7 and CRF8 duplicates. Multiple genetic manipulations revealed that only POS1 and Capsicum POS1 (CaPOS1) functioned in fruit size control via the positive regulation of cell expansion. Comparative studies in a phylogenetic framework showed the directional enhancement of POS1-like expression in the flowers and fruits of Physaleae and the specific gain of certain interacting proteins associated with cell expansion by POS1 and CaPOS1. A lineage-specific single nucleotide polymorphism (SNP) caused the 68th amino acid histidine in the POS1 orthologs of non-Physaleae (Nicotiana and Solanum) to change to arginine in Physaleae (Physalis and Capsicum). Substituting the arginine in Physaleae POS1-like by histidine completely abolished their function in the fruits and the protein-protein interaction (PPI) with calreticulin-3. Transcriptomic comparison revealed the potential downstream pathways of POS1, including the brassinosteroid biosynthesis pathway. However, POS1-like may have functioned ancestrally in abiotic stress within Solanaceae. Our work demonstrated that heterometric expression and a SNP caused a single amino acid change to establish new PPIs, which contributed to the co-option of POS1 in multiple regulatory pathways to regulate cell expansion and thus fruit size in Physaleae. These results provide new insights into fruit morphological evolution and fruit yield control.

A Nomogram for Predicting Event-Free Survival in Childhood Acute Lymphoblastic Leukemia: A Multicenter Retrospective Study.

Objective: Even though childhood acute lymphoblastic leukemia (ALL) has an encouraging survival rate in recent years, some patients are still at risk of relapse or even death. Therefore, we aimed to construct a nomogram to predict event-free survival (EFS) in patients with ALL. Method: Children with newly diagnosed ALL between October 2016 and July 2021 from 18 hospitals participating in the South China children's leukemia Group (SCCLG) were recruited and randomly classified into two subsets in a 7:3 ratio (training set, n=1187; validation set, n=506). Least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were adopted to screen independent prognostic factors. Then, a nomogram can be build based on these prognostic factors to predict 1-, 2-, and 3-year EFS. Concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance and clinical utility of nomogram. Result: The parameters that predicted EFS were age at diagnosis, white blood cell at diagnosis, immunophenotype, ETV6-RUNX1/TEL-AML1 gene fusion, bone marrow remission at day 15, and minimal residual disease at day 15. The nomogram incorporated the six factors and provided C-index values of 0.811 [95% confidence interval (CI) = 0.792-0.830] and 0.797 (95% CI = 0.769-0.825) in the training and validation set, respectively. The calibration curve and AUC revealed that the nomogram had good ability to predict 1-, 2-, and 3-year EFS. DCA also indicated that our nomogram had good clinical utility. Kaplan-Meier analysis showed that EFS in the different risk groups stratified by the nomogram scores was significant differentiated. Conclusion: The nomogram for predicting EFS of children with ALL has good performance and clinical utility. The model could help clinical decision-making.

TaMOR is essential for root initiation and improvement of root system architecture in wheat.

Optimal root system architecture is beneficial for water-fertilizer use efficiency, stress tolerance and yield improvement of crops. However, because of the complexity of root traits and difficulty in phenotyping deep roots, the study on mechanisms of root development is rarely reported in wheat (Triticum aestivum L.). In this study, we identified that the LBD (LATERAL ORGAN BOUNDARIES DOMAIN) gene TaMOR (MORE ROOT in wheat) determines wheat crown root initiation. The mor mutants exhibited less or even no crown root, dwarfism, less grain number and lodging caused by few roots. The observation of cross sections showed that crown root initiation is inhibited in the mor mutants. Molecular assays revealed that TaMOR interacts with the auxin response factor ARF5 to directly induce the expression of the auxin transporter gene PIN2 (PIN-FORMED 2) in the root base to regulate crown root initiation. In addition, a 159-bp MITE (miniature inverted-repeat transposable element) insertion causing DNA methylation and lower expression of TaMOR-B was identified in TaMOR-B promoter, which is associated with lower root dry weight and shorter plant height. The results bring new light into regulation mechanisms of crown root initiation and offer a new target for the improvement of root system architecture in wheat.

The Physalis floridana genome provides insights into the biochemical and morphological evolution of Physalis fruits.

The fruits of Physalis (Solanaceae) have a unique structure, a lantern-like fruiting calyx known as inflated calyx syndrome (ICS) or the Chinese lantern, and are rich in steroid-related compounds. However, the genetic variations underlying the origin of these characteristic traits and diversity in Physalis remain largely unknown. Here, we present a high-quality chromosome-level reference genome assembly of Physalis floridana (~1.40 Gb in size) with a contig N50 of ~4.87 Mb. Through evolutionary genomics and experimental approaches, we found that the loss of the SEP-like MADS-box gene MBP21 subclade is likely a key mutation that, together with the previously revealed mutation affecting floral MPF2 expression, might have contributed to the origination of ICS in Physaleae, suggesting that the origination of a morphological novelty may have resulted from an evolutionary scenario in which one mutation compensated for another deleterious mutation. Moreover, the significant expansion of squalene epoxidase genes is potentially associated with the natural variation of steroid-related compounds in Physalis fruits. The results reveal the importance of gene gains (duplication) and/or subsequent losses as genetic bases of the evolution of distinct fruit traits, and the data serve as a valuable resource for the evolutionary genetics and breeding of solanaceous crops.

Prognostic Value and Outcome for ETV6/RUNX1-Positive Pediatric Acute Lymphoblastic Leukemia: A Report From the South China Children's Leukemia Group.

PURPOSE: To analyzed the outcome of ETV6/RUNX1-positive pediatric acute B lymphoblastic leukemia (B-ALL) with the aim of identifying prognostic value. METHOD: A total of 2,530 pediatric patients who were diagnosed with B-ALL were classified into two groups based on the ETV6/RUNX1 status by using a retrospective cohort study method from February 28, 2008, to June 30, 2020, at 22 participating ALL centers. RESULTS: In total, 461 (18.2%) cases were ETV6/RUNX1-positive. The proportion of patients with risk factors (age <1 year or ≥10 years, WB≥50×109/L) in ETV6/RUNX1-positive group was significantly lower than that in negative group (P<0.001), while the proportion of patients with good early response (good response to prednisone, D15 MRD < 0.1%, and D33 MRD < 0.01%) in ETV6/RUNX1-positive group was higher than that in the negative group (P<0.001, 0.788 and 0.004, respectively). Multivariate analysis of 2,530 patients found that age <1 or ≥10 years, SCCLG-ALL-2016 protocol, and MLL were independent predictor of outcome but not ETV6/RUNX1. The EFS and OS of the ETV6/RUNX1-positive group were significantly higher than those of the negative group (3-year EFS: 90.11 ± 4.21% vs 82 ± 2.36%, P<0.0001, 3-year OS: 91.99 ± 3.92% vs 88.79 ± 1.87%, P=0.017). Subgroup analysis showed that chemotherapy protocol, age, prednisone response, and D15 MRD were important factors affecting the prognosis of ETV6/RUNX1-positive children. CONCLUSIONS: ETV6/RUNX1-positive pediatric ALL showed an excellent outcome but lack of independent prognostic significance in South China. However, for older patients who have the ETV6/RUNX1 fusion and slow response to therapy, to opt for more intensive treatment.

Encephalopathy and brain atrophy during induction chemotherapy in acute lymphoblastic leukemia.

The MRI showed encephalopathy and brain atrophy of the left parietal lobe, occipital lobe and temporal lobe and decreased infiltration of the dura mater on T2-weighted imaging. But encephalopathy and brain atrophy could be improved with neurotrophic drugs and additional intelligence teaching.

Improved social force model considering conflict avoidance.

The social force model (SFM) can be applied to characterize pedestrian dynamics in normal scenarios. However, its model of interactions among pedestrians deviates from actual scenarios to some extent. Thus, we propose an improved SFM where pedestrians consider avoiding potential conflicts in advance during the walking process. Meanwhile, the response range of potential conflicts is related to the response time and relative velocity vector. Simulation results demonstrate that the conflict avoidance force plays an important role in guiding pedestrian dynamics. Conflict avoidance makes pedestrian trajectories smoother and more realistic. Moreover, for high pedestrian density (without congestion), moderate values of response time may exist, resulting in the minimum evacuation efficiency. We hope to provide some insights into how to better model interactions among pedestrians during normal evacuation.

Two Novel AP2/EREBP Transcription Factor Genes TaPARG Have Pleiotropic Functions on Plant Architecture and Yield-Related Traits in Common Wheat.

AP2/EREBPs play significant roles in plant growth and development. A novel, pleiotropic TaPARG (PLANT ARCHITECTURE-RELATED GENE), a member of the AP2/EREBP transcription factor gene family, and its flanking sequences were isolated in wheat (Triticum aestivum L.). Two TaPARG genes were identified and named as TaPARG-2A and TaPARG-2D. Their amino acid sequences were highly similar especially in the functional domains. TaPARG-2A on chromosome 2A was flanked by markers Xwmc63 and Xgwm372. TaPARG-2D was mapped to chromosome 2D. Subcellular localization revealed that TaPARG-2D was localized in the nucleus. The results of tissue expression pattern, overexpression in rice, association analysis and distinct population verification jointly revealed that TaPARG functions during the entire growth cycle of wheat. Its functions include regulation of plant architecture-related and yield-related traits. Association analysis, geographic distribution and allelic frequencies suggested that favored haplotypes Hap-2A-2 and Hap-2A-3 were selected in Chinese wheat breeding programs. Both favored haplotypes might be caused by a single amino acid substitution (His/Tyr). These results suggest that TaPARG is a regulatory factor in plant growth and development, and that the favored alleles might be useful for improving plant architecture and grain yield of wheat.

Overexpression of wheat gene TaMOR improves root system architecture and grain yield in Oryza sativa.

Improved root architecture is an effective strategy to increase crop yield. We demonstrate that overexpression of transcription factor gene MORE ROOT (TaMOR) from wheat (Triticum aestivum L.) results in more roots and higher grain yield in rice (Oryza sativa). TaMOR, encoding a plant-specific transcription factor belonging to the ASYMMETRIC LEAVES2/LATERAL ORGAN BOUNDARIES (AS2/LOB) protein family, is highly conserved in wheat and its wild relatives. In this study, tissue expression patterns indicated that TaMOR mainly localizes to root initiation sites. The consistent gene expression pattern suggests that TaMOR is involved in root initiation. Exogenous auxin treatment induced TaMOR expression without de novo protein biosynthesis. Both in vivo and in vitro experiments demonstrated that TaMOR interacts with TaMOR-related protein TaMRRP, which contains a four-tandem-pentatricopeptide repeat motif. Overexpression of TaMOR led to more lateral roots in Arabidopsis thaliana, and TaMOR-overexpressing rice plants had more crown roots, a longer main panicle, a higher number of primary branches on the main panicle, a higher grain number per plant, and higher yield per plant than the plants of wild type. In general, TaMOR-D-overexpressing lines had larger root systems in Arabidopsis and rice, and produce a higher grain yield per plant. TaMOR therefore offers an opportunity to improve root architecture and increase yield in crop plants.

[Study of traditional Chinese medicine syndrome on multiple organ dysfunction syndrome in the elderly].

OBJECTIVE: To statistically analyze the clinical data from patients with multiple organ dysfunction syndrome in the elderly (MODSE), and to investigate the distribution pattern of traditional Chinese medicine (TCM) syndromes. METHODS: TCM data of 200 patients with MODSE was collected on 1, 3 and 7 days after diagnosis. Using 134 symptoms as observation indexes, clustering analysis was used to analyze the TCM symptoms and syndromes of these patients. RESULTS: In accordance with Diagnostic efficacy of standard TCM Syndrome, Diagnostics of TCM, State Standard of the People's Republic of China: clinical diagnose and treat Terminology of TCM, expert group differentiate on the professional knowledge and clinical manifestation and 7 types of TCM syndrome were selected. Among all syndrome types, there were 134 (22.3%) cases of phlegm stagnation with the largest population, 113 cases (18.8%) of toxic heat flourishing, 97 cases (16.2%) of damp-heat accumulation, 85 cases (14.2%) of qi-deficiency, 67 cases (11.2%) of both yin and yang deficiency, 55 cases (9.2%) of fu being filled and substances could not pass through, and 48 cases (8.1%) of qi stagnation and blood stasis. CONCLUSIONS: This preliminary study found 7 primary types of TCM syndrome in patients with MODSE, including syndrome of phlegm stagnation, toxic heat flourishing, accumulation of damp-heat, qi-deficiency, both yin and yang deficiency, fu being filled and substances could not pass through and qi stagnation and blood stasis. The most common syndrome is phlegm stagnation and deficiency, phlegm, blood stasis, toxic are the main etiology and pathology of the disease.

[Study of using shattering extraction with solvent to extract ingredient of three kinds of traditional Chinese medicine].

OBJECTIVE: To prove if it is possible for using the shattering extraction with solvent to extract ingredients of traditional Chinese medicine. METHOD: The shattering extraction with solvent, the refluxing extraction and the ultrasonic extraction were used to extract paeoniflorin from Radix Paeoniae rubra, and to extract baicalein from Radix Scutellariae, and to extract chlorogenic acid from Flos lonicerae japonicae respectively, using ingredient content and extract yield as the measuring indexes. RESULT: The content of each every ingredient obviously higher by using shattering extraction with solvent than using refluxing extraction or the ultrasonic extraction. CONCLUSION: The shattering extraction with solvent is a high efficiency, simple and quick extraction. It may be used to extract the ingredient of three kinds of traditional Chinese medicine.