SZ-685C inhibits the growth of non-functioning pituitary adenoma by down-regulating miR-340-3p and inducing autophagy.

Background: SZ-685C, an anthracycline compound derived from the mangrove endophytic fungus Halorosellinia sp. (No. 1403) collected from the South China Sea, has shown strong anticancer activities. Non-functioning pituitary adenomas (NFPAs) are a type of tumor that can be challenging to manage clinically and have a significant unmet medical need. Our research has found that SZ-685C showed an inhibitory effect on the viability, migration ability, and proliferation ability of a human non-functioning pituitary tumor-derived folliculostellate (PDFS) cell line. Methods: SZ-685C was prepared and purified from the mangrove endophytic fungus No. 1403. PDFS cells were exposed to SZ-685C, and the effect of SZ-685C on PDFS cells was evaluated. RNA sequencing was used to analyze the miRNA expression profile in PDFS cells of the control group and SZ-685C-treated group. Quantitative polymerase chain reaction (qPCR) was performed to verify the expression of selected miR-340-3p. The effects of SZ-685C on PDFS cells after overexpression of miR-340-3p were evaluated. Dual-luciferase reporter assays showed PPP1CB is a direct target of miR-340-3p. Finally, the action pathway of the selected miR-340-3p was predicted and evaluated through bioinformatics analysis. Results: SZ-685C reduced cell viability in PDFS cells, accompanied by inhibition of migration ability and proliferation ability. The IC50 value for 24 h is 9.144 ± 0.991 µM, and for 48 h is 4.635 ± 0.551 µM. SZ-685C increased the protein levels of Beclin 1, the ratio of LC3-II to LC3-I, and LAMP-1, and down-regulated p62. MiRNA sequencing and further validation showed that miR-340-3p significantly decreased in PDFS cells treated with SZ-685C. After overexpression of miR-340-3p, the inhibition of viability, migration ability, proliferation ability, and autophagy-promoting effect of SZ-685C on PDFS cells were weakened. SZ-685C caused a decrease in PPP1CB expression and activation of the ERK pathway in PDFS cells, and this trend was reversed after overexpression of miR-340-3p. Conclusions: SZ-685C downregulates the expression of miR-340-3p in PDFS cells, thereby reducing the expression of PPP1CB and activating the ERK pathway to promote autophagic cell death, leading to inhibition of PDFS cell growth.

Induction of apoptosis by oridonin in nonfunctioning pituitary adenoma cells.

Nonfunctioning pituitary adenoma (NFPA) is one of the major subtypes of pituitary adenomas (PA) and its primary treatment is surgical resection. However, normal surgery fails to remove lesions completely and there remains in lack of frontline treatment, so the development of new drugs for NFPA is no doubt urgent. Oridonin (ORI) has been reported to have antitumor effects on a variety of tumors, but whether it could exhibit the same effect on NFPA requires to be further investigated. The effects of ORI on pituitary-derived folliculostellate cell line (PDFS) cell viability, colony formation, proliferation ability, migration, and invasion were examined by Cell Counting Kit-8, colony formation assay, 5­Ethynyl­2'­deoxyuridine proliferation assay, wound-healing assay, and Transwell assay. The differentially expressed genes in the control and ORI-treated groups were screened by transcriptome sequencing analysis and analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. Cell cycle analysis was performed to detect changes in cell cycle. Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to detect apoptosis in ORI-treated cells. Western blot assay was performed to detect Bax, Bcl-2, and cleaved Caspase-3 protein expression. ORI inhibited PDFS cell viability and significantly suppressed cell proliferation, migration, and invasion. GO and KEGG results showed that ORI was associated with signaling pathways such as cell cycle and apoptosis in PDFS cells. In addition, ORI blocked cells in G2/M phase and induced apoptosis in PDFS cells. ORI can trigger cell cycle disruption and apoptosis collaboratively in PDFS cells, making it a promising and effective agent for NFPA therapy.

MicroRNAs: A novel signature in the metastasis of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor, characterized by squamous cell differentiation, it is the sixth leading cause of cancer-related deaths globally. The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered, coupled with higher risk of metastasis, which is an exceedingly malignant characteristic of cancer, frequently leading to a high mortality rate. Unfortunately, there is currently no specific and effective marker to predict and treat metastasis in ESCC. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, approximately 22 nucleotides in length. miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence, progression, and prognosis of cancer. Here, we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis, and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors. This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis, with the ultimate aim of reducing the mortality rate among patients with ESCC.

Association of spinal-pelvic parameters with recurrence of lumbar disc herniation after endoscopic surgery: a retrospective case-control study.

PURPOSE: This study aimed to investigate the relationship between spinal-pelvic parameters and recurrence of lumbar disc herniation (rLDH) after percutaneous endoscopic lumbar discectomy (PELD) through a retrospective case-control study. METHODS: Patients who underwent PELD for single-segment LDH at our hospital were included in this study. The relationship between sagittal balance parameters of the spine and recurrence was analysed through correlation analysis, and ROC curves were plotted. The baseline characteristics, sagittal balance parameters of the spine and radiological parameters of the case and control groups were compared, and the relationship between sagittal balance parameters of the spine and recurrence of rLDH after PELD was determined through univariate and multivariate logistic regression analysis. RESULTS: Correlation analysis showed that PI and ∆PI-LL were negatively correlated with grouping (r = -0.090 and -0.120, respectively, P = 0.001 and 0.038). ROC curve analysis showed that the area under the curve (ROC-AUC) for predicting rLDH based on PI was 0.65 (CI95% = 0.598, 0.720), with a cut-off of 50.26°. The ROC-AUC for predicting rLDH based on ∆PI-LL was 0.56 (CI95% = 0.503, 0.634), with a cut-off of 28.21°. Multivariate logistic regression analysis showed that smoking status (OR = 2.667, P = 0.008), PI ≤ 50.26 (OR = 2.161, P = 0.009), ∆PI-LL ≤ 28.21 (OR = 3.185, P = 0.001) and presence of Modic changes (OR = 4.218, P = 0.001) were independent risk factors, while high DH (OR = 0.788, P = 0.001) was a protective factor. CONCLUSION: PI < 50.26 and ∆PI-LL < 28.21 were risk factors for recurrence of lumbar disc herniation after spinal endoscopic surgery and had some predictive value for post-operative recurrence.

Efficacy and safety comparison of infrared laser moxibustion and traditional moxibustion in knee osteoarthritis: study protocol for a Zelen-design randomized controlled non-inferiority clinical trial.

BACKGROUND: Knee osteoarthritis (KOA) is the most common chronic degenerative joint disease and places a substantial burden on the public health resources in China. The purpose of this study is to preliminarily evaluate whether infrared laser moxibustion (ILM) is non-inferior to traditional moxibustion (TM) in the treatment of KOA. MATERIALS AND METHODS: In the designed Zelen-design randomized controlled non-inferiority clinical trial, a total of 74 patients with KOA will be randomly allocated to one of two interventions: ILM treatment or TM treatment. All participants will receive a 6-week treatment and a follow-up 4 weeks after treatment. The primary outcomes will be the mean change in pain scores on the numeric rating scale (NRS) measured at baseline and the end of last treatment at week 6. The secondary outcomes will be the pain scores on the NRS from weeks 1 to 5 after the start of treatment and the changes from baseline to endpoints (weeks 6 and 10) in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), SF-36, knee circumference, and 6-min walking test. In addition, safety assessment will be performed throughout the trial. CONCLUSION: The results of our study will help determine whether a 6-week treatment with ILM is non-inferior to TM in patients with KOA, therefore providing evidence to verify if ILM can become a safer alternative for TM in clinical applications in the future. TRIAL REGISTRATION: Clinical Trial Registration Platform (ChiCTR2200065264); Pre-results. Registered on 1 November 2022.

Advances in Point-of-Care Testing of microRNAs Based on Portable Instruments and Visual Detection.

MicroRNAs (miRNAs) are a class of small noncoding RNAs that are approximately 22 nt in length and regulate gene expression post-transcriptionally. miRNAs play a vital role in both physiological and pathological processes and are regarded as promising biomarkers for cancer, cardiovascular diseases, neurodegenerative diseases, and so on. Accurate detection of miRNA expression level in clinical samples is important for miRNA-guided diagnostics. However, the common miRNA detection approaches like RNA sequencing, qRT-PCR, and miRNA microarray are performed in a professional laboratory with complex intermediate steps and are time-consuming and costly, challenging the miRNA-guided diagnostics. Hence, sensitive, highly specific, rapid, and easy-to-use detection of miRNAs is crucial for clinical diagnosis based on miRNAs. With the advantages of being specific, sensitive, efficient, cost-saving, and easy to operate, point-of-care testing (POCT) has been widely used in the detection of miRNAs. For the first time, we mainly focus on summarizing the research progress in POCT of miRNAs based on portable instruments and visual readout methods. As widely available pocket-size portable instruments and visual detection play important roles in POCT, we provide an all-sided discussion of the principles of these methods and their main limitations and challenges, in order to provide a guide for the development of more accurate, specific, and sensitive POCT methods for miRNA detection.

Moxibustion ameliorated age-related alterations in neurological behavior and gut microbiota in mice.

OBJECTIVE: To observe the anti-aging effects of moxibustion on age-related alterations in middle-aged mice. METHODS: Thirty, 9-month-old, male ICR mice were randomly divided into the moxibustion and control groups (N = 15). Mice in the moxibustion group were given mild moxibustion at the Guanyuan acupoint for 20 minutes every other day. After 30 treatments, neurobehavior tests, lifespan, gut microbiota composition and splenic gene expression were observed in the mice. RESULTS: Moxibustion improved the locomotor activity as well as motor function, activated the SIRT1-PPARα signaling pathway, ameliorated age-related alterations in gut microbiota, and affected the expression of genes related to energy metabolism in spleen. CONCLUSION: Moxibustion ameliorated age-related alterations in neurobehavior and gut microbiota in middle-aged mice.

Exosomal noncoding RNAs in central nervous system diseases: biological functions and potential clinical applications.

Central nervous system (CNS) disease is a general term for a series of complex and diverse diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), CNS tumors, stroke, epilepsy, and amyotrophic lateral sclerosis (ALS). Interneuron and neuron-glia cells communicate with each other through their homeostatic microenvironment. Exosomes in the microenvironment have crucial impacts on interneuron and neuron-glia cells by transferring their contents, such as proteins, lipids, and ncRNAs, constituting a novel form of cell-to-cell interaction and communication. Exosomal noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and PIWI-interacting RNAs (piRNAs), regulate physiological functions and maintain CNS homeostasis. Exosomes are regarded as extracellular messengers that transfer ncRNAs between neurons and body fluids due to their ability to cross the blood-brain barrier. This review aims to summarize the current understanding of exosomal ncRNAs in CNS diseases, including prospective diagnostic biomarkers, pathological regulators, therapeutic strategies and clinical applications. We also provide an all-sided discussion of the comparison with some similar CNS diseases and the main limitations and challenges for exosomal ncRNAs in clinical applications.

Comparison of the supraglottic airway device BlockBusterTM and laryngeal mask airway Supreme in anaesthetised, paralyzed adult patients: a multicenter randomized controlled trial.

BACKGROUND: This multicenter prospective, randomized controlled clinical trial compared the clinical performance of supraglottic airway device (SAD) BlockBusterTM and laryngeal mask airway (LMA) Supreme for airway maintenance in anesthetized, paralyzed adult patients. METHODS: A total of 651 adult patients scheduled for elective surgery in 13 hospitals were randomly allocated into BlockBuster group (n = 351) or Supreme group (n = 300). The primary outcome was oropharyngeal leak pressure (OLP). Duration and ease of insertion, fiberscopic view of positioning, airway manipulations, and complications were also assessed. RESULTS: The OLP was significantly higher in BlockBuster group compared with Supreme group (29.9 ± 4.2 cmH2O vs 27.4 ± 4.3 cmH2O, p < 0.001). Success rate of insertion at the first attempt (90.2% vs 85.1%, p = 0.027), rate of optimal fiberscopic view (p = 0.002) and satisfactory positioning of SAD (p < 0.001) were significantly increased in BlockBuster group. CONCLUSIONS: Both SAD BlockBusterTM and LMA Supreme are safe, effective, and easy-to-use devices for airway maintenance in anesthetized, paralyzed adult patients, but the SAD BlockBusterTM is superior to LMA Supreme in terms of OLP, success rate at the first attempt, and fiber-optic view of positioning. TRIAL REGISTRATION: The trial is registered at www.chictr.org.cn (ChiCTR-ONC-16009105).

Optimization of Tokuhashi Scoring System to Improve Survival Prediction in Patients with Spinal Metastases.

INTRODUCTION: Predicting survival time for patients with spinal metastases is important in treatment choice. Generally speaking, six months is a landmark cutoff point. Revised Tokuhashi score (RTS), the most widely used scoring system, lost its accuracy in predicting 6-month survival, gradually. Therefore, a more precise scoring system is urgently needed. OBJECTIVE: The aim of this study is to create a new scoring system with a higher accuracy in predicting 6-month survival based on the previously used RTS. METHODS: Data of 171 patients were examined to determine factors that affect prognosis (reference group), and the remaining (validation group) were examined to validate the reliability of a new score, adjusted Tokuhashi score (ATS). We compared their discriminatory abilities of the prediction models using area under receiver operating characteristic curve (AUC). RESULTS: Target therapy and the Z score of BMI (Z-BMI), which adjusted to the patients' sex and age, were additional independent prognostic factors. Patients with target therapy use are awarded 4 points. The Z score of BMI could be added directly to yield ATS. The AUCs were 0.760 for ATS and 0.636 for RTS in the validation group. CONCLUSION: Appropriate target therapy use can prolong patients' survival. Z-BMI which might reflect nutritional status is another important influencing factor. With the optimization, surgeons could choose a more individualized treatment for patients.

Adverse cardiovascular effects and potential molecular mechanisms of DEHP and its metabolites-A review.

Currently, cardiovascular disease (CVD) is a health hazard that is associated with progressive deterioration upon exposure to environmental pollutants. Di(2-ethylhexyl) phthalate (DEHP) has been one of the focuses of emerging concern due to its ubiquitous nature and its toxicity to the cardiovascular (CV) system. DEHP has been noted as a causative risk factor or a risk indicator for the initiation and augment of CVDs. DEHP represents a precursor that contributes to the pathogenesis of CVDs through its active metabolites, which mainly include mono (2-ethylhexyl) phthalate (MEHP). Herein, we systematically presented the association between DEHP and its metabolites and adverse CV outcomes and discussed the corresponding effects, underlying mechanisms and possibly interventions. Epidemiological and experimental evidence has suggested that DEHP and its metabolites have significant impacts on processes and factors involved in CVD, such as cardiac developmental toxicity, cardiac injury and apoptosis, cardiac arrhythmogenesis, cardiac metabolic disorders, vascular structural damage, atherogenesis, coronary heart disease and hypertension. DNA methylation, PPAR-related pathways, oxidative stress and inflammation, Ca2+ homeostasis disturbance may pinpoint the relevant mechanisms. The preventive and therapeutic measures are potentially related with P-glycoprotein, heat-shock proteins, some antioxidants, curcumin, apigenin, ß-thujaplicin, glucagon-like peptide-1 receptor agonists and Ang-converting enzyme inhibitors and so on. Promisingly, future investigations should aid in thoroughly assessing the causal relationship and molecular interactions between CVD and DEHP and its metabolites and explore feasible prevention and treatment measures accordingly.

Downregulation of Fat Mass and Obesity-Related Protein in the Anterior Cingulate Cortex Participates in Anxiety- and Depression-Like Behaviors Induced by Neuropathic Pain.

N6-methyladenosine (m6A) is the most abundant methylation modification on mRNA in mammals. Fat mass and obesity-related protein (FTO) is the main RNA m6A demethylase. FTO is involved in the occurrence and maintenance of neuropathic pain (NP). NP often induces mental disorders. We found that NP downregulated the expression of FTO in the anterior cingulate cortex (ACC), inhibited the expression of matrix metalloproteinase-9 (MMP-9) in the ACC, maladjusted the brain-derived neurotrophic factor precursor (proBDNF) and mature brain-derived neurotrophic factor (mBDNF) levels in the ACC, and induced anxiety- and depression-like behaviors in mice. Blocking the downregulation of FTO in the ACC induced by peripheral nerve injury could reverse the anxiety- and depression-like behaviors of mice. Contrarily, downregulation of simulated FTO induced anxiety- and depression-like behaviors in mice. After peripheral nerve injury, the binding of FTO to MMP-9 mRNA decreased and the enrichment of m6A on MMP-9 mRNA increased. In conclusion, downregulation of FTO in ACC by regulating MMP-9 mRNA methylation level contributes to the occurrence of anxiety- and depression-like behaviors in NP mice.

Chemotherapy or Allogeneic Stem Cell Transplantation as Salvage Therapy for Patients with Refractory Acute Myeloid Leukemia: A Multicenter Analysis.

INTRODUCTION: The overall outcome of patients with refractory AML (rAML) remains poor. Though allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered as the only curative therapy, it is routinely recommended only for patients after remission with salvage chemotherapy. OBJECTIVE: In this study, we evaluated the impact of salvage chemotherapy or allo-HSCT on the overall outcome in rAML. METHODS: We collected the clinical data of 220 patients from 4 medical centers and performed retrospective analysis of prognosis factors, including salvage chemotherapy, intensity of chemotherapy, and allo-HSCT. RESULTS: A total of 29 patients received allo-HSCT directly without salvage chemotherapy, 26 patients achieved complete remission (CR) or complete remission with incomplete hematological recovery (CRi) after transplantation and 4-year leukemia-free survival (LFS) and overall survival (OS) were 45.0 ± 10.7 and 51.0 ± 10.6%, respectively. Another 191 patients received salvage chemotherapy and 81 (42.2%) achieved CR or CRi. Thirty-four patients among them underwent subsequent allo-HSCT with 4-year LFS and OS of 46.0 ± 8.8 and 46.2 ± 9.0%. The 4-year LFS and OS in 26 patients who failed to obtain CR or CRi but received allo-HSCT with active disease were 32.9 ± 10.0 and 36.9 ± 10.8%, respectively. For patients who received salvage chemotherapy but not allo-HSCT, few of them became long-term survivors. In multivariate analysis, salvage chemotherapy and the intensity of chemotherapy failed to have significant impact on both OS and LFS. Allo-HSCT was the only prognostic factor for improved OS and LFS in multivariate analysis. CONCLUSIONS: These results indicate the benefit of allo-HSCT in patients with rAML and direct allo-HSCT without salvage chemotherapy could be treatment option.

Research progress of CO2 oxidative dehydrogenation of propane to propylene over Cr-free metal catalysts.

CO2-assisted oxidative dehydrogenation of propane (CO2-ODHP) is an attractive strategy to offset the demand gap of propylene due to its potentiality of reducing CO2 emissions, especially under the demands of peaking CO2 emissions and carbon neutrality. The introduction of CO2 as a soft oxidant into the reaction not only averts the over-oxidation of products, but also maintains the high oxidation state of the redox-active sites. Furthermore, the presence of CO2 increases the conversion of propane by coupling the dehydrogenation of propane (DHP) with the reverse water gas reaction (RWGS) and inhibits the coking formation to prolong the lifetime of catalysts via the reverse Boudouard reaction. An effective catalyst should selectively activate the C-H bond but suppress the C-C cleavage. However, to prepare such a catalyst remains challenging. Chromium-based catalysts are always applied in industrial application of DHP; however, their toxic properties are harmful to the environment. In this aspect, exploring environment-friendly and sustainable catalytic systems with Cr-free is an important issue. In this review, we outline the development of the CO2-ODHP especially in the last ten years, including the structural information, catalytic performances, and mechanisms of chromium-free metal-based catalyst systems, and the role of CO2 in the reaction. We also present perspectives for future progress in the CO2-ODHP.

Decreased psoas muscle area is a prognosticator for 90-day and 1-year survival in patients undergoing surgical treatment for spinal metastasis.

BACKGROUND AND AIMS: Survival estimation for patients with spinal metastasis is crucial to treatment decisions. Psoas muscle area (PMA), a surrogate for total muscle mass, has been proposed as a useful survival prognosticator. However, few studies have validated the predictive value of decreased PMA in an Asian cohort or its predictive value after controlling for existing preoperative scoring systems (PSSs). In this study, we aim to answer: (1) Is PMA associated with survival in Han Chinese patients with spinal metastasis? (2) Is PMA a good prognosticator according to concordance index (c-index) and decision curve analysis (DCA) after controlling for six existing and commonly used PSSs? METHODS: This study included 180 adult (≥18 years old) Taiwanese patients with a mean age of 58.3 years (range: 22-85) undergoing surgical treatment for spinal metastasis. A patient's PMA was classified into decreased, medium, and large if it fell into the lower (0-33%), middle (33-67%), and upper (67-100%) 1/3 in the study cohort, respectively. We used logistic and cox proportional-hazard regressions to assess whether PMA was associated with 90-day, 1-year, and overall survival. The model performance before and after addition of PMA to six commonly used PSSs, including Tomita score, original Tokuhashi score, revised Tokuhashi score, modified Bauer score, New England Spinal Metastasis Score, and Skeletal Oncology Research Group machine learning algorithms (SORG-MLAs), was compared by c-index and DCA to determine if PMA was a useful survival prognosticator. RESULTS: Patients with a larger PMA is associated with better 90-day, but not 1-year, survival. The model performance of 90-day survival prediction improved after PMA was incorporated into all PSSs except SORG-MLAs. PMA barely improved the discriminatory ability (c-index, 0.74; 95% confidence interval [CI], 0.67-0.82 vs. c-index, 0.74; 95% CI, 0.66-0.81) and provided little gain of clinical net benefit on DCA for SORG-MLAs' 90-day survival prediction. CONCLUSIONS: PMA is a prognosticator for 90-day survival and improves the discriminatory ability of earlier-proposed PSSs in our Asian cohort. However, incorporating PMA into more modern PSSs such as SORG-MLAs did not significantly improve its prediction performance.

[Dynamic Material Flow Analysis of Perfluorooctane Sulfonate in China: 1985-2019].

Perfluorooctane sulfonates (PFOS) are regarded as a category of chemicals with persistence, bioaccumulation, and toxicity. Understanding dynamic flows, stocks, and emissions of PFOS on a macro spatial and temporal scale can help provide a scientific basis for their sound management. In this work, a dynamic material flow analysis (d-MFA) model was built to characterize and analyze the cycles of PFOS in mainland China over the period 1985-2019. Flows, stocks, and environmental emissions were calculated and the sensitivity and uncertainty of the results were then analyzed. Results show that domestic production was the primary source of PFOS in China, most of which was flowed to the domestic market in the form of final products, with the remainder exported to international markets; soil and water were the main sinks of PFOS in China, with emissions from the usage stage contributing the largest portion (103 tons in 2019). The number of inflows and outflows were relatively low before 2000, but gradually increased until 2009 when the relevant convention was issued. Since 2005, in-use stocks and emissions of PFOS have grown yearly. In addition, stocks in landfill have been climbing since 1985. End-of-life management was still dominated by traditional methods, such as landfill and incineration, while there was a trend towards green treatments. This study can provide basic data and theoretical support for the sound management of PFOS in China.

FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia.

Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient-derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase-activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation-harboring leukemias.

Comparative study on the curative effect of laparoscopic nephron sparing surgery and renal functions under selective segmental renal artery clamping and main renal artery clamping.

OBJECTIVE: To discuss the clinical effect and safety evaluation of laparoscopic nephron sparing surgery (LNSS) under selective segmental renal artery clamping (SSRAC) and main renal artery clamping (MRAC). METHODS: Eighty-four patients with T1 localized renal tumors who were admitted and treated from October 2017 to October 2018 were retrospectively analyzed, and they were classified into the S group (42 patients) and M group (42 patients). The patients in the S group received LNSS under SSRAC, while the patients in the M group received LNSS under MRAC. The duration of the operation, amount of intraoperative blood loss, intraoperative warm ischemia time, duration of postoperative hospital stay and positive rate of incisal edge; the serum creatinine and blood urea nitrogen values before and after the operation; and the occurrence rates of intraoperative and postoperative complications were compared. RESULTS: All operations were completed smoothly. No patients had a positive incisal edge, and no patients were converted to MRAC during the operation. The duration of the operation and the amount of intraoperative blood loss increased in the S group compared with the M group. The differences were statistically significant (P <0.05). The differences in the intraoperative warm ischemia time, postoperative drainage and duration of postoperative hospital stay in both groups had no statistical significance (P >0.05). The differences in serum creatinine (SCr) and blood urea nitrogen (BUN) in both groups before the operation had no statistical significance (P >0.05). The SCr and BUN levels significantly increased 1 d and 1 m after the operation. The SCr and BUN levels 1 d and 1 m after the operation were significantly lower in the S group than in the M group, and the differences were statistically significant (P <0.05). The differences in the occurrence rates of intraoperative and postoperative complications in both groups had no statistical significance (P >0.05). CONCLUSION: SSRAC is a new renal artery clamping technology, and its curative effect on LNSS patients is significant. In addition, SSRAC has high safety and little influence on renal functions.

Effects of soil-incorporated plant litter morphological characteristics on the soil detachment process in grassland on the Loess Plateau of China.

The Loess Plateau of China is one of the most eroded areas in the world. In the past 20 years, effective vegetation restoration measures have significantly changed the near-surface characteristics of soil. In natural conditions, plant litter is widespread in the topsoil. The effects of litter incorporated into soil on the process of soil detachment, which is closely related to plant litter morphology, are still not well known. This study aimed to detect the variation of litter morphological characteristics and quantify their effects on soil detachment capacity and rill erodibility when litter is incorporated into the soil. Four plant litters (Bothriochloa ischaemum (L.) Keng., Artemisia sacrorum Ledeb., Setaria viridis (L.) Beauv., and Artemisia capillaris Thunb.) with five length levels (<0.5, 0.5-2, 2-4, 4-6, and 6-8 cm) were incorporated into soil (idle for 50 days) at the same litter biomass rate (0.7 kg m-2). Then the soil was sampled and cores were subjected to overland flow under six flow shear stress levels (5.66, 8.31, 12.21, 15.55, 19.15 and, 22.11 Pa) using a hydraulic flume (4.0 m × 0.35 m). The results showed that the litter morphological characteristics of litter length density (LLD), litter surface area density (LSAD) and litter volume ratio (LVR) differed in plant species at the same litter biomass rate. Correspondingly, soil detachment capacity (ranging from 0.414 to 2.179 kg m-2 s-1) and rill erodibility (ranging from 0.037 to 0.177 s m-1) varied significantly and mean values from the Bothriochloa ischaemum (L.) Keng. treatments were the minimums, which were 28% to 37% and 23% to 35% less than that of the other treatments, respectively. The soil detachment capacity and rill erodibility were significantly correlated with the litter morphological characteristics of LLD, LSAD and LVR (p < 0.01). The contact area between litter and soil was the most critical factor affecting soil detachment. Incorporated plant litter residue litter effect on rill erodibility could be well estimated by LSAD.