Azacitidine combined with interferon-α for pre-emptive treatment of AML/MDS after allogeneic peripheral blood stem cell transplantation: A prospective phase II study.

This prospective clinical study aimed to evaluate the efficacy and safety of the pre-emptive treatment modality of azacitidine in combination with interferon-α (IFN-α) in AML/MDS patients post-transplantation. Forty-seven patients aged 17-62 were enrolled with 14 patients having completed the planned 12 cycles. Following initiation, 72.3% responded positively after the first cycle, peaking at 77.2% by the fifth cycle. Notably, 24 patients maintained sustained responses throughout a median follow-up of 1050 days (range, 866-1234). Overall survival, leukaemia-free survival and event-free survival probabilities at 3 years were 69.5%, 60.4% and 35.7% respectively. Cumulative incidences of relapse and non-relapse mortality were 36.5% and 4.3% respectively. Multivariate analysis identified that receiving pre-emptive treatment for fewer than six cycles and the absence of chronic graft-versus-host disease after intervention was significantly associated with poorer clinical outcomes. The combination of azacitidine with IFN-α was well-tolerated with no observed severe myelotoxicity, and the majority of adverse events were reversible and manageable. In conclusion, the use of azacitidine in conjunction with IFN-α as pre-emptive therapy is a safe and effective treatment to prevent disease progression in AML/MDS patients with MRD positivity post-allo-HSCT.

Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells.

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCLX L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-XL and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) primary samples, and in vivo patient-derived xenograft AML models. We further demonstrated the senolytic activity of 753B, which enhanced the efficacy of chemotherapy by targeting chemotherapy-induced cellular senescence. These results provide a pre-clinical rationale for the utility of 753B in AML therapy, and suggest that 753B could produce an added therapeutic benefit by overcoming cellular senescence-induced chemoresistance when combined with chemotherapy.

Construction and verification of aggressive behavior risk prediction model in stable patients with schizophrenia.

BACKGROUND: Among all types of mental disorders, individuals with schizophrenia exhibit the highest frequency of aggressive behavior. This disrupts the healthcare environment and poses threats to family life and social harmony. Present approaches fail to identify individuals with schizophrenia who are predisposed to aggressive behavior. In this study, we aimed to construct a risk prediction model for aggressive behavior in stable patients with schizophrenia, which may facilitate early identification of patients who are predisposed to aggression by assessing relevant factors, enabling the management of high-risk groups to mitigate and prevent aggressive behavior. METHODS: A convenience sample of stable inpatients with schizophrenia were selected from Daqing Municipal Third Hospital and Chifeng Municipal Anding Hospital from March 2021 to July 2023. A total of 429 patients with stable schizophrenia who met the inclusion criteria were included. A survey was conducted with them using a questionnaire consisting of general information questionnaire, Positive and Negative Symptom Scale, Childhood Trauma Questionnaire-Short Form, Connor-Davidson Resilience Scale and Self-esteem Scale. Patients enrolled in this study were divided into aggressive and non-aggressive groups based on whether there was at least one obvious and recorded personal attack episode (including obvious wounding and self-injurious behavior) following diagnosis. Binary Logistic regression was used to determine the influencing factors, and R software was used to establish a nomogram model for predicting the risk of aggressive behavior. Bootstrap method was used for internal validation of the model, and the validation group was used for external validation. C statistic and calibration curve were used to evaluate the prediction performance of the model. RESULTS: The model variables included Age, Duration of disease, Positive symptom, Childhood Trauma, Self-esteem and Resilience. The AUROC of the model was 0.790 (95% CI:0.729-0.851), the best cutoff value was 0.308; the sensitivity was 70.0%; the specificity was 81.4%; The C statistics of internal and external validation were 0.759 (95%CI:0.725-0.814) and 0.819 (95%CI:0.733-0.904), respectively; calibration curve and Brier score showed good fit. CONCLUSIONS: The prediction model has a good degree of discrimination and calibration, which can intuitively and easily screen the high risk of aggressive behavior in stable patients with schizophrenia, and provide references for early screening and intervention.

Associations between perceived overqualification, transformational leadership and burnout in nurses from intensive care units: A multicentre survey.

AIMS: To explore whether perceived overqualification increases the risk of burnout and whether transformational leadership negatively moderates this relationship. BACKGROUND: Perceived overqualification might contribute to burnout and lead to poor experience of transformational leadership, and transformational leadership might be associated with burnout. However, these relationships have not yet been confirmed. METHODS: A multicentre cross-sectional study. A total of 321 nurses from intensive care units were recruited from six tertiary hospitals. Scale of Perceived OverQualification, Transformational Leadership Questionnaire and emotional exhaustion subscale of the Maslach Burnout Inventory-General Survey were employed to collect the data. Hierarchical multiple regression and bootstrap resampling were applied to analyse the data. RESULTS: Burnout was positively associated with perceived overqualification and negatively associated with transformational leadership (each p < 0.05). Transformational leadership significantly mediated the relationship between perceived overqualification and burnout (b = -0.6389, 95% confidence interval: -0.8706, -0.4072). CONCLUSION: Our findings indicated that perceived overqualification and transformational leadership directly or indirectly affect burnout among nurses from intensive care units. IMPLICATIONS FOR NURSING MANAGERS: Personal and organizational-oriented interventions utilizing nurses' overall qualifications and implementing transformational leadership should be employed by nurse managers to alleviate burnout and promote the work performance of nurses from intensive care units.

Stable Atropine Loaded Film As a Potential Ocular Delivery System For Treatment Of Myopia.

PURPOSE: The objective of the present study was to prepare stable and high bioavailability ocular atropine loaded films (ATR-films) as potential ocular drug delivery systems for the treatment of myopia. METHODS: ATR-films were prepared by the solvent casting method and the physical properties of films were evaluated including thickness, water content, light transparency, disintegration time, and mechanical properties. FT-IR, DSC, XRD, TGA, AFM, and Raman spectroscopy were performed to characterize the film. The stability test was conducted under different conditions, such as high humidity, high temperature, and strong light. The pharmacokinetic study and irritation assessment were conducted in rabbits. The efficacy of ATR-films was evaluated by refraction and ocular biometry in myopia guinea pigs. RESULT: After optimizing the formulation, the resulting ATR-film was flexible and transparent with lower water content (8.43% ± 1.25). As expected, the ATR-film was stable and hydrolysate was not detected, while the content of hydrolysate in ATR eye drops can reach up to 8.1867% (limit: < 0.2%) in the stability study. The safety assessment both in vitro and in vivo confirmed that the ATR-film was biocompatible. Moreover, the bioavailability (conjunctiva 3.21-fold, cornea 2.87-fold, retina 1.35-fold, sclera 2.05-fold) was greatly improved compared with the ATR eye drops in vivo pharmacokinetic study. The pharmacodynamic study results showed that the ATR-film can slow the progress of form-deprivation myopia (~ 100 ± 0.81D), indicating that it has a certain therapeutic effect on form-deprivation myopia. CONCLUSION: The ATR-film with good stability and high bioavailability will have great potential for the treatment of myopia.

ViTT: Vision Transformer Tracker.

This paper presents a new model for multi-object tracking (MOT) with a transformer. MOT is a spatiotemporal correlation task among interest objects and one of the crucial technologies of multi-unmanned aerial vehicles (Multi-UAV). The transformer is a self-attentional codec architecture that has been successfully used in natural language processing and is emerging in computer vision. This study proposes the Vision Transformer Tracker (ViTT), which uses a transformer encoder as the backbone and takes images directly as input. Compared with convolution networks, it can model global context at every encoder layer from the beginning, which addresses the challenges of occlusion and complex scenarios. The model simultaneously outputs object locations and corresponding appearance embeddings in a shared network through multi-task learning. Our work demonstrates the superiority and effectiveness of transformer-based networks in complex computer vision tasks and paves the way for applying the pure transformer in MOT. We evaluated the proposed model on the MOT16 dataset, achieving 65.7% MOTA, and obtained a competitive result compared with other typical multi-object trackers.

Prevalence of sexual dysfunction in Chinese patients with schizophrenia: a systematic review and meta-analysis.

Background: There may be a higher risk of sexual dysfunction in the schizophrenia population. China has made significant contributions to the global community of patients with schizophrenia. Currently, there is no estimation of the prevalence of sexual dysfunction in Chinese patients with schizophrenia. Aim: We conducted a meta-analysis to pool the evaluated prevalence of sexual dysfunction in Chinese patients with schizophrenia. Methods: We systematically searched PubMed, Web of Science, Embase, PsycINFO, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Medical Network, and Huayi Academic Literature Database from inception to September 2023. Meta-analysis was conducted with R version 4.3.1. Outcomes: To examine the pooled prevalence of sexual dysfunctions among Chinese patients with schizophrenia. Results: In our meta-analysis, we included 16 studies with 5417 participants, among whom 1727 experienced sexual dysfunction. The results of the meta-analysis reveal that the prevalence of sexual dysfunction in Chinese patients with schizophrenia is 50.43% (95% CI, 37.86%-62.95%). Subgroup analysis results indicate that various factors-including the specific type of dysfunction, duration of illness, assessment tools, mean ages, study region, gender, research setting, marital status, publication years, and type of antipsychotics-all have a particular impact on the occurrence rate of sexual dysfunction in Chinese patients with schizophrenia. Female patients had a slightly higher prevalence of sexual dysfunction than male patients (65.22% vs 54.84%). Clinical Implications: The findings of this study can be used in high-quality nursing care for the schizophrenia population, particularly for the care of specific sexual dysfunction nursing. Strengths and Limitations: This meta-analysis is the first to evaluate the prevalence of sexual dysfunction in China among patients with schizophrenia. The limited number of studies is the most important limitation. Conclusions: The pooled prevalence of sexual dysfunction in Chinese patients with schizophrenia is relatively high, and the prevention and intervention of individual sexual dysfunctions in schizophrenia are advised.

Experiences of returning to work in patients with schizophrenia after treatment: A longitudinal qualitative study.

BACKGROUND: Returning to work (RTW) has always been regarded as one of the important indicators to evaluate the therapeutic effect of patients with schizophrenia. The existing studies on RTW in patients with schizophrenia are mostly focused on intervention measures, and the qualitative research on RTW is very limited. The purpose of this study was to evaluate the experience of the RTW after treatment in patients with schizophrenia. METHOD: A longitudinal qualitative study was conducted involving 24 patients with schizophrenia in China. The interviews were held at three time-points during their RTW process, (1) when patients had improved and were close to discharge, (2) within 1 month post-discharge, and (3) 6 months post-discharge. The interview recordings were transcribed by the research team, and transcripts were independently analyzed by two independent coders using reflexive thematic analysis. RESULTS: A total of 24 patients with schizophrenia participated in 72 personal interviews. The thematic framework based on the experience of patients with schizophrenia reveals a three-phases of the process of RTW: improved, being at a loss, and job crisis. The study identified one theme of the first phase: the expectation and optimism. Two themes in the second phase: (1) psychological distress of upcoming work; (2) expectation of assistance pre-work. And four themes in the third phase: (1) tremendous pressure of RTW; (2) lack of medical and social support; (3) social status and interpersonal relationships change; and (4) high level of financial pressure. CONCLUSION: The experience of RTW is a dynamic process with great challenges in each phase, patients with schizophrenia have been deeply affected by what they have experienced. There is an urgent need to ensure that existing community and social support is integrated into daily care to support patients with schizophrenia to RTW successful. The findings of this study also suggest relevant departments and employers should be aware of the barriers to RTW for patients with schizophrenia, and take certain measures to change the current situation.

[Application of PROTACs in Hematological Malignancies--Review].

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules by utilizing the ubiquitin proteasome system (UPS) to degrade proteins of interest. PROTACs have exhibited unprecedented efficacy and specificity in degrading various oncogenic proteins because of their unique mechanism of action, ability to target "undruggable" and mutant proteins. A series of PROTACs have been developed to degrade multiple key protein targets for the treatment of hematologic malignancy. Notably, PROTACs that target BCL-XL, IRAK4, STAT3 and BTK have entered clinical trials. The known PROTACs that have the potential to be used to treat various hematological malignancies are systematically summarized in this review.

Adsorption performance and optimization by response surface methodology on tetracycline using Fe-doped ZIF-8-loaded multi-walled carbon nanotubes.

Herein, an iron-doped ZIF-8-loaded multi-walled carbon nanotube (FZM) was synthesized and its adsorption performance on tetracycline (TC) was investigated. The experimental conditions (solution pH, temperature, adsorbent dose) were optimized by Box-Behnken design (BBD) in response surface methodology (RSM). The results show that the adsorption effect of TC by FZM is optimal under the conditions of temperature = 298 K, pH = 6, and contact time = 360 min. The adsorption processes of TC by FZM follow the pseudo-second-order (PSO) kinetic and Freundlich isotherm models, indicating that chemisorption is the dominant factor and the adsorption reaction is multi-layer, with a theoretical maximum saturation capacity of 1111.11 mg/g at 298 K. The adsorption thermodynamic results indicate that the adsorption of TC by FZM is a spontaneous and endothermic process. The mechanism of TC adsorption by FZM possibly occurs through hydrogen bonding, surface complexation, π-π interaction, and electrostatic interaction. From the statistical results, the optimal adsorption capacity of TC by FZM is 599.78 mg/g at a pH of 7.1, a temperature of 312.5 K, and an adsorbent dose of 64.43 mg/L, with a deviation of 1.73% from the actual value. Furthermore, regeneration experiments demonstrate that FZM has excellent reusability with a 15% loss of adsorption capacity after four cycles. This study provides some insights to study the adsorption behavior of TC by MOFs and the optimization of the adsorption experimental conditions, and also shows the potential of FZM for TC removal.

Diagnostic challenge in mixed phenotype acute leukemia with T/megakaryocyte or T/myeloid lineages accompanied by t(3;3).

BACKGROUND: The diagnosis of mixed phenotype acute leukemia (MPAL) with T/megakaryocyte or T/myeloid lineages accompanied by t(3;3) is always a challenge. Therefore, multiple experimental methods are usually required to avoid misdiagnosis. In this report, we presented a rare case of MPAL with T/myeloid lineages accompanied by t(3;3) and discussed the experience of differential diagnosis and our appreciation of the MPAL with T/megakaryocyte and T/myeloid lineages accompanied by t(3;3). CASE PRESENTATION: A 31-year-old woman was admitted to our hospital due to recurrent fever for 20 days. Two distinct blast populations were detected by flow cytometry analysis: one population fulfills the immunophenotypic criteria for T-lymphoblastic leukemia, while the other population is highly suggestive of megakaryoblasts. These immunophenotypic features support the diagnosis of MPAL (T/megakaryocyte), which is rarely reported​. Interestingly, a complex karyotype was detected afterward by cytogenetics with t(3;3)(q21;q26.2), indicating a diagnosis of AML with t(3;3), a subset of which is also characterized by megakaryocytic markers such as CD41 and CD61. It seems that the second blast population detected by flow cytometry could not be classified into either diagnosis based on the morphology, immunophenotyping, and even cytogenetic findings, posing a real diagnostic problem because of the lack of clear-cut cytogenetic morphological defined criteria to distinguish between acute megakaryocytic leukemia and AML with t(3;3). Combining all of the examination data, this case was ultimately diagnosed as MPAL (T + My)-NOS with t(3;3) through differential diagnosis. Before the cytogenetic results were available, the patient received an acute lymphoblastic leukemia (ALL) regimen for MPAL treatment, but the effect was unsatisfactory. After the diagnosis was clear, she received an AML-like regimen with azacitidine for 7 days and venetoclax for 14 days, and achieved complete morphological remission. CONCLUSION: MPAL with either T/megakaryocyte or T/myeloid lineages accompanied by t(3;3) is rare, and it is difficult to make a clear diagnosis. Thus, comprehensive examinations, including bone marrow cell morphology, flow cytometry analysis, cytogenetics, and molecular analysis are recommended to avoid misdiagnosis. AML-like regimen including azacitidine and venetoclax may be effective for treating MPAL (T + My)-NOS with t(3;3).

Study on natural frequency response characteristics of coal vibration excited by simple harmonic wave.

The natural frequency of coal is one of the important technical parameters for the application of the permeability enhancement technology of coal and rock forced vibration. Aiming at exploring the dominant frequency of the permeability enhancement technology of coal vibration excited by vibration wave, the model of coal vibration excited by simple harmonic wave (SHW) was constructed. Furthermore, considering the three main control parameters, i.e., excitation force, coal sample size and mechanical parameters, the response characteristics of coal vibration excited by SHW were simulated and calculated. The calculation results demonstrate that when the frequency of excitation force equals the natural frequency of coal, the vibration occurs and the peak values of response parameters all increase significantly. The peak acceleration response of coal increases with the increase of excitation force, whereas it decreases with the increase of coal size. Under the same SHW excitation force, the mechanical parameters of coal determine the vibration response characteristics of coal, and the natural frequency of coal is proportional to the elastic modulus. Finally, the variation law of natural frequency response characteristics of coal vibration excited by SHW was verified by the response experiment on coal vibration under SHW excitation and related test results. The research results can serve as a theoretical basis for the application of the permeability enhancement technology of coal vibration excited by vibration wave.

Development of a nurse-manager dualistic intervention program to alleviate burnout among nurses based on the appreciative inquiry.

Aims: To develop a feasible and effective nurse-manager dualistic intervention program to support nurses coping with burnout symptoms. Background: Person-organization combined interventions were recommended as the most effective approach for reducing burnout symptoms. However, few interventions have been developed in the nursing field. Methods: The Medical Research Council, United Kingdom (MRC UK), Framework for Development and Evaluation of Complex Interventions, was employed for nurse-manager dualistic intervention program development. The following three steps were followed for developing the dualistic intervention program: (1) identifying the evidence base by conducting extensive reviews of the relevant literature and a mixed study; (2) identifying/developing a theory by selecting the job demands-resources model and proposing the theoretical framework for intervention development; and (3) modifying the process and outcomes of the nurse-manager dualistic intervention program. Results: The intervention program consists of six group sessions over 9 weeks. Researchers/managers are supposed to deliver the program. The main contents of the intervention are (1) inception (session 1); (2) discovery (session 2); (3) dream (session 3); (4) design (session 4); (5) destiny (session 5); and (6) keep (session 6). The emphasis of the intervention is on helping nurses dealing with burnout symptoms. Conclusion: Following the guidance of the MRC framework, a feasible and potentially effective nurse-manager dualistic intervention program was developed for nurses coping with burnout. Future studies are needed to model the intervention and assess the effects and replicability of the intervention.

Comparison of multi-omics results between patients with acute myeloid leukemia with long-term survival and healthy controls.

Background: Acute myeloid leukemia (AML) is a group of highly heterogeneous diseases, for which approximately 35-40% of patients younger than 60 years old can be cured. However, the multi-omics characteristics and immune cell infiltration (ICI) status of adult long-term survival patients with AML patients compared with healthy controls are still relatively under-explored. Methods: A total of 10 healthy transplant donors (control group) and 11 long-term survival patients with AML with de novo sampling from 2019 to 2020 at the Institute of Hematology in the Hospital of Blood Diseases were enrolled. We simultaneously performed 850 K methylation and bulk RNA-seq on these 21 patients for comparing the differential gene methylation and expression levels between the two groups. The analysis of immune cell gene expression was based on 4 algorithms single sample gene set enrichment analysis (ssGSEA), EPIC, ESTIMATE and immunophenotype score (IPS) on the bulk RNA-seq data. Results: The differential methylation positions (DMPs) of the control group was significantly higher than that of the long-term survival group (P<0.01). The hypomethylated probes for Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment is summarized as follows: the significant pathway was related to NK-cell-mediated cytotoxicity and amino acid metabolism. We also found the Differential expression genes (DEGs) of long-term survival AML were roughly similar, and the DEGs were highly relevant to the cellular amino acid metabolic process pathway by gene set enrichment analysis (GSEA). Based on the further univariate and multivariate Cox survival analyses in GSE37642, genes crosslinked of DEGs and DMPs: LOXL1 and PDZRN4, which characterized as hypomethylated and upregulated, may become an AML prognostic marker (P<0.05). Besides, compared with the long-term-survival AML patients who discontinued chemotherapy after >3 years and the healthy donors, T cell-, natural killer cell-, MHC- and effector cell (EC)-related genes were downregulated; suppressor cells (SC) and checkpoint (CP) cells were significantly upregulated in the long-term-survival AML patients who discontinued chemotherapy after <3 years. Conclusions: In terms of DNA methylation, RNA expression and ICI, AML patients with long-term survival were slightly different than that of healthy people. The profile of long-term AML survivors, especially those who discontinued chemotherapy less than 3 years, still differed from that of healthy people.

Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia.

Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2-selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance of RAS/MAPK activation, we found by single-cell DNA sequencing rapid clonal selection of RAS-mutated clones in AML patients treated with VEN-containing regimens. In summary, these findings establish RAS/MAPK/MCL-1 and mitochondrial fitness as key survival mechanisms of VEN-RE AML and provide the rationale for combinatorial strategies effectively targeting these pathways.

Effects of different aberrations in the CRLF2 gene on the biological characteristics and drug sensitivities of Nalm6 cells.

INTRODUCTION: To investigate the effects and mechanism of action of upregulated CRLF2 expression resulting from different aberrations in the CRLF2 gene (CRLF2, CRLF2 + IK6, P2RY8-CRLF2 and CRLF2 F232C) in the B cell ALL cell line Nalm6. METHODS: Cell proliferation was measured using cell counting kit-8. Transcriptome sequencing technology (RNA-seq) was used to compare changes in gene expression resulting from different aberrations in CRLF2. High-throughput drug sensitivity testing was used to determine the drug sensitivity of cells. RESULTS: All four aberrations in CRLF2 upregulated CRLF2 expression and promoted the proliferation of Nalm6 cells. The RNA-seq results showed the upregulation of genes in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and the downregulation of genes in the cell cycle pathway in the CRLF2 F232C-overexpressing cells. Western blotting showed that the expression of p-STAT5 protein was significantly higher in the CRLF2 F232C-overexpressing cells. Cells with aberrations in CRLF2 were more resistant to cyclophosphamide and drugs commonly used during treatment than cells in the vector group. The half-maximal inhibitory concentration (IC50 or GI50 ) of dexamethasone was significantly higher in the CRLF2 F232C-overexpressing cell line. CONCLUSIONS: The overexpression of CRLF2, CRLF2 + IK6, P2RY8-CRLF2 and CRLF2 F232C promotes the proliferation of Nalm6 cells, activates the JAK/STAT signalling pathway and leads to a reduction in sensitivity towards various chemotherapeutic drugs.

Local drug delivery systems as therapeutic strategies against periodontitis: A systematic review.

Periodontitis is a chronic inflammation of the soft tissue surrounding and supporting the teeth, which causes periodontal structural damage, alveolar bone resorption, and even tooth loss. Its prevalence is very high, with nearly 60% of the global population affected. Hence, periodontitis is an important public health concern, and the development of effective healing treatments for oral diseases is a major target of the health sciences. Currently, the application of local drug delivery systems (LDDS) as an adjunctive therapy to scaling and root planning (SRP) in periodontitis is a promising strategy, giving higher efficacy and fewer side effects by controlling drug release. The cornerstone of successful periodontitis therapy is to select an appropriate bioactive agent and route of administration. In this context, this review highlights applications of LDDS with different properties in the treatment of periodontitis with or without systemic diseases, in order to reveal existing challenges and future research directions.

Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity.

PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.

[Clinical Characteristics of Patients with Ph+ Mixed Phenotype Acute Leukemia].

OBJECTIVE: To investigate the clinical biological characteristics and prognosis of the patients with mixed phenotype acute leukemia with t(9;22)(q34;q11.2) and/or BCRABL1 (Ph+ MPAL). METHODS: The morphological, immunological, cytogenetic, and molecular features of 33 in patients with Ph+ MPAL were retrospectively analyzed in our center from June 2002 to June 2016 according to the scoring proposal of European Group for the Classification of Acute Leukemia(EGIL )1998 and WHO 2008 criteria. All the cases were either treated with acute lymphoblastic leukemia (ALL) induction regimen or combined chemotherapy regimens for both acute lymphoblastic and acute myeloid leukemia,part of which also received tyrosine kinase inhibitor(TKI) and 5 cases underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) after complete remission. RESULTS: Ph+ MPAL occurred predominantly in male patients (ratio of M/F was 1.75∶1), and a high WBC counts at diagnosis; the WBC count was higher than 30×109/L in 25 patients( 75.8% )， and appeared higher than 100 ×109/L in 13 patients ( 39.4%). Among all the 33 Ph+MPAL patients, 32 (97.0%) had a myeloid / B-lymphoid (M/B) phenotype， and 1 case(3.0%) had a myeloid/ B-lymphoid/ T-lymphoid/ (M/B/T) phenotype. There was no patients displayed myeloid / T-lymphoid (M/T) or B-lymphoid/ T-lymphoid/ (B/T) phenotype. 19 of all cases(57.6%) met the diagnosis criteria of Ph+MPAL based on EGIL 1998 criteria, while the remaining 14 cases can be diagnosed as Ph+ MPAL by WHO 2008 classification,but excluded as Ph+MAPL by EGIL 1998.Karyotype analysis was successfully performed in 31 cases, and out of them 13 (41.9%) had a sole Ph chromosome, 10 (32.3%) had additional chromosome aberration and Ph chromosome was not found in 8 cases (25.8%) .In 31 patients the fusion gene BCR/ABL (P190、P210) was detected,including 17 (54.8%) cases with the p190 BCR/ABL transcript, 8 (25.8%) cases with the p210 BCR/ABL transcript, 4 (12.9%) expressing both transcripts and 2 (6.5%) without any one of these 2 transcripts. 24 out of 33 patients (77.4%) achieved complete remission after induction therapy. The median time achieving CR was 43(26-98)days. The CR rate of patients treated with and without imatinib after the first inducion treatment was 81.3% and 46.7%,respectively (P+0.05). Within the 17 patients treated with imatinib at induction stage，2 of which became BCR/ABLnegative．At consolidation chemotherapy stage, 9 out of 16 patients became BCR/ABL negative, including 3 patients already subjected to HSCT. The median time reached to BCR/ABL negative was 2.87（1.13-9.20）months. CONCLUSION: Ph+ MPAL is more common in male, and inclined to high WBC counts at diagnosis. Myeloid/B lymphoid phenotype is more common, and the prognosis of patients with Ph+MPAL is poor. Imatinib and allogeneic hematopoietic stem cell transplantation may improve survival of patients with Ph+MPAL.