Nano-Enhanced Phase Reinforced Magnesium Matrix Composites: A Review of the Matrix, Reinforcement, Interface Design, Properties and Potential Applications.

Magnesium matrix composites are essential lightweight metal matrix composites, following aluminum matrix composites, with outstanding application prospects in automotive, aerospace lightweight and biomedical materials because of their high specific strength, low density and specific stiffness, good casting performance and rich resources. However, the inherent low plasticity and poor fatigue resistance of magnesium hamper its further application to a certain extent. Many researchers have tried many strengthening methods to improve the properties of magnesium alloys, while the relationship between wear resistance and plasticity still needs to be further improved. The nanoparticles added exhibit a good strengthening effect, especially the ceramic nanoparticles. Nanoparticle-reinforced magnesium matrix composites not only exhibit a high impact toughness, but also maintain the high strength and wear resistance of ceramic materials, effectively balancing the restriction between the strength and toughness. Therefore, this work aims to provide a review of the state of the art of research on the matrix, reinforcement, design, properties and potential applications of nano-reinforced phase-reinforced magnesium matrix composites (especially ceramic nanoparticle-reinforced ones). The conventional and potential matrices for the fabrication of magnesium matrix composites are introduced. The classification and influence of ceramic reinforcements are assessed, and the factors influencing interface bonding strength between reinforcements and matrix, regulation and design, performance and application are analyzed. Finally, the scope of future research in this field is discussed.

Development Trend in Composition Optimization, Microstructure Manipulation, and Strengthening Methods of Die Steels under Lightweight and Integrated Die Casting.

In the general environment of lightweight automobiles, the integrated die-casting technology proposed by Tesla has become the general mode to better achieve weight reduction in automobiles. The die-casting mold required by integrated die-casting technology has the characteristics of large scale and complexity. Hence, higher requirements are put forward for the comprehensive performance of the die steel. Despite the stagnation in the progress of conventional strengthening methods, enhancing the performance of die steel has become increasingly challenging. Indeed, it necessitates exploring novel die steel and optimizing heat treatment and reinforcement technologies. This article summarizes and analyzes the development status of die steel and corresponding heat treatment and microstructure manipulation as well as strengthening methods and elaborates on an excellent nano-strengthening technology. Furthermore, this review will aid researchers in establishing a comprehensive understanding of the development status of die steel and the processes utilized for its strengthening. It will also assist them in developing die steel with improved comprehensive performance to meet the high demand for mold steel in the integrated die-casting technology of the new era.

A compendium of mitochondrial molecular characteristics provides novel perspectives on the treatment of rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is an autoimmune disease that exhibits a high degree of heterogeneity, marked by unpredictable disease flares and significant variations in the response to available treatments. The lack of optimal stratification for RA patients may be a contributing factor to the poor efficacy of current treatment options. The objective of this study is to elucidate the molecular characteristics of RA through the utilization of mitochondrial genes and subsequently construct and authenticate a diagnostic framework for RA. Mitochondrial proteins were obtained from the MitoCarta database, and the R package limma was employed to filter for differentially expressed mitochondrial genes (MDEGs). Metascape was utilized to perform enrichment analysis, followed by an unsupervised clustering algorithm using the ConsensuClusterPlus package to identify distinct subtypes based on MDEGs. The immune microenvironment, biological pathways, and drug response were further explored in these subtypes. Finally, a multi-biomarker-based diagnostic model was constructed using machine learning algorithms. Utilizing 88 MDEGs present in transcript profiles, it was possible to classify RA patients into three distinct subtypes, each characterized by unique molecular and cellular signatures. Subtype A exhibited a marked activation of inflammatory cells and pathways, while subtype C was characterized by the presence of specific innate lymphocytes. Inflammatory and immune cells in subtype B displayed a more modest level of activation (Wilcoxon test P < 0.05). Notably, subtype C demonstrated a stronger correlation with a superior response to biologics such as infliximab, anti-TNF, rituximab, and methotrexate/abatacept (P = 0.001) using the fisher test. Furthermore, the mitochondrial diagnosis SVM model demonstrated a high degree of discriminatory ability in distinguishing RA in both training (AUC = 100%) and validation sets (AUC = 80.1%). This study presents a pioneering analysis of mitochondrial modifications in RA, offering a novel framework for patient stratification and potentially enhancing therapeutic decision-making.

The Role of Lithium in the Aging Precipitation Process of Al-Zn-Mg-Cu Alloys and Its Effect on the Properties.

It is well known that the development of lightweight alloys with improved comprehensive performance and application value are the future development directions for the ultra-high-strength 7xxx series Al-Zn-Mg-Cu alloys used in the aircraft field. As the lightest metal element in nature, lithium (Li) has outstanding advantages in reducing the density and increasing the elastic modulus in aluminum alloys, so Al-Zn-Mg-Cu alloys containing Li have gained widespread attention. Furthermore, since the Al-Zn-Mg-Cu alloy is usually strengthened by aging treatment, it is crucial to understand how Li addition affects its aging precipitation process. As such, in this article, the effects and mechanism of Li on the aging precipitation behavior and the impact of Li content on the aging precipitation phase of Al-Zn-Mg-Cu alloys are briefly reviewed, and the influence of Li on the service properties, including mechanical properties, wear resistance, and fatigue resistance, of Al-Zn-Mg-Cu alloys are explained. In addition, the corresponding development prospects and challenges of the Al-Zn-Mg-Cu-Li alloy are also proposed. This review is helpful to further understand the role of Li in Al-Zn-Mg-Cu alloys and provides a reference for the development of high-strength aluminum alloys containing Li with good comprehensive properties.

Phase I study of MSB2311, a novel pH-dependent anti-PD-L1 monoclonal antibody, treating patients with advanced solid tumors and lymphoma.

MSB2311 is a novel pH-dependent humanized anti-programmed death-ligand 1 (PD-L1) monoclonal antibody. This phase I study primarily aimed to determine the maximum tolerated dose (MTD)/recommended phase 2 dose level (RP2D) of MSB2311 in patients with advanced solid tumors or lymphoma. MSB2311 was intravenously administered at 3, 10, and 20 mg/kg every 3 weeks (Q3W) and 10 mg/kg every 2 weeks (Q2W) using 3 + 3 design. During expansion phase, eligible patients with either PD-L1 overexpression, Epstein-Barr Virus positive, microsatellite instability high/mismatch repair deficient, or high tumor mutation burden tumors were treated at RP2D. A total of 37 Chinese patients were treated, including 31 with solid tumors and 6 lymphoma. No dose limiting toxicity was reported and MTD was not reached. The trial was expanded at 20 mg/kg Q3W or 10 mg/kg Q2W, both of which were determined as RP2D. Most common drug-related treatment-emergent adverse events were anemia (43.2%), aspartate aminotransferase increase (27.0%), proteinuria (21.6%), alanine aminotransferase increase and hypothyroidism (18.9% each), thyroid stimulating hormone increased and hyperglycemia (16.2% each). Out of 20 efficacy evaluable patients with biomarker positive solid tumors, 6 achieved confirmed partial response with the median duration of response of 11.0 months (95% CI 7.0-11.4) and 4 had stable disease, resulting an objective response rate of 30.0% (95% CI 11.9, 54.3) and disease control rate of 50.0% (95% CI 27.2, 72.8). One partial response was also observed among 6 patients with lymphoma. MSB2311 demonstrated a manageable safety profile and promising antitumor activity in patients with advanced solid tumors and lymphomas.

Up-regulation of microRNA-183 reduces FOXO1 expression in gastric cancer patients with Helicobacter pylori infection.

The aim of the study is to detect the expression of FOXO1 mRNA and protein in samples from gastric cancer patients with Helicobacter pylori (H. pylori) infection, and to investigate the relationship between FOXO1 expression and miR-183 expression. Twenty-six gastric cancer patients with H. pylori infection and 26 gastric cancer patients without H. pylori infection were included into experimental group and control group, respectively. Tumor tissues and peripheral blood were collected from all subjects. QRT-PCR was used to determine the expression of miRNA and mRNA. Western blotting was carried out to measure protein expression. Dual luciferase reporter assay was used to identify direct interaction between miRNA and 3'-UTR of mRNA. Cell proliferation was examined by CCK-8 assay. FOXO1 mRNA and protein expression was down-regulated in gastric cancer patients, being possibly related to H. pylori infection. The expression of miR-183 in tumor tissues and serum from gastric cancer patients with H. pylori infection was elevated, and probably regulated the expression of FOXO1 by direct targeting. Stimulation by H. pylori up-regulated the expression of miR-183 in gastric cancer AGS cells, and reduced the levels of FOXO1 mRNA and protein. Inhibition of miR-183 elevated the expression of FOXO1 and suppressed the proliferation of AGS cells. The present study demonstrates that the expression of FOXO1 in tumor tissues and blood from gastric cancer patients with H. pylori infection is significantly down-regulated, and may be related to the up-regulation of miR-183. H. pylori may regulate FOXO1 expression through miR-183 to affect the pathological process of gastric cancer.

Potential role of 25(OH)D insufficiency in the dysfunction of glycolipid metabolism and cognitive impairment in patients with T2DM.

Purpose: To investigate the changes of plasma 25(OH)D levels in type 2 diabetes mellitus (T2DM) patients and explore its role in the dysfunction of glucose and lipid metabolism and cognition. Methods: One hundred and thirty-two T2DM patients were enrolled and the demographic and clinical data were collected. The plasma concentration of 25(OH)D was detected and the patients were divided into two groups including a Vitamin D insufficient (VDI) group and a normal VD group according to the clinical diagnostic criterial of VDI with the plasma 25(OH)D level less than 29 ng/mL. The glycolipid metabolic and routine blood biochemical indices were detected, the plasma concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble myeloid soluble trigger receptor 1 (sTREM1) were measured. The cognitive function was assessed using the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). The depressive symptomatology was assessed using the Center for Epidemiological Survey Depression Scale (CES-D). Sleep quality was assessed using the Pittsburgh sleep quality index (PSQI). Results: There were 70 T2DM patients with VDI (70/132, 53.03%) in this study. The plasma concentrations of glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial blood glucose (PBG), IL-6, and sTREM1 were remarkably increased in T2DM patients with VDI as compared with that with the normal VD, accompanied with an elevated BRIEF-A scores. There was no significant difference between groups with regard to the indices of blood lipid, liver function, and scores in CES-D and PSQI. Moreover, results of Pearson correlation test showed that the plasma 25(OH)D levels were negatively correlated with HbA1c, FPG, PBG, CRP, IL-6, sTREM1, CES-D sum scores, and PSQI sum scores, but positively correlated with the plasma levels of Serum creatinine (Scr). Furthermore, result of Receiver Operating Characteristic (ROC) curve analysis showed a predictive role of VDI levels in discriminating T2DM patients with higher cognitive impairments, with the sensitivity and specificity being 62.12% and 62.12%, respectively. Conclusion: VDI is harmful for T2DM patients with a significant relation with the hyperglycosemia and cognitive dysfunction.

MRCP Combined With CT Promotes the Differentiation of Benign and Malignant Distal Bile Duct Strictures.

OBJECTIVE: To determine whether contrast-enhanced computed tomography (CT) can promote the identification of malignant and benign distal biliary strictures (DBSs) compared to the use of magnetic resonance cholangiopancreatography (MRCP) alone and to identify imaging findings of malignant DBSs. MATERIALS AND METHODS: A total of 168 consecutive patients with confirmed DBSs were reviewed. MRCP alone and MRCP combined with CT images were blindly analyzed by two radiologists (e.g., stricture pattern, margins), and malignant or benign DBSs were identified based on surgical findings, endoscopy findings, or follow-up. The diagnostic accuracy of the two reviewers using MRCP alone and MRCP combined with CT were evaluated. MRCP and CT features of malignant and benign DBSs were compared using multiple logistic regression analysis to identify independent malignant risk factors. RESULTS: MRCP combined with CT examination could improve the diagnostic accuracy, which increased from 70.2% to 81.5% in Doctor A and from 85.1% to 89.3% in Doctor B. The multiple logistic regression model revealed that stricture length [odds ratio (OR) 1.070, P=0.016], angle of the DBS (OR 1.061, P<0.001), double duct sign (OR 4.312, P=0.003) and low density in the arterial phase (OR 0.319, P=0.018) were associated with malignant DBS. A scoring model incorporating these four factors was established; at a threshold value of 1.75, and the sensitivity and specificity for the detection of malignant DBSs were 73.5 and 85.9%, respectively. CONCLUSIONS: Compared to the use of MRCP alone, MRCP combined with contrast-enhanced CT can improve the accuracy of DBS diagnosis. The scoring model accurately predicts malignant DBSs and helps make treatment decisions.

Predicting intraventricular hemorrhage growth with a machine learning-based, radiomics-clinical model.

We constructed a radiomics-clinical model to predict intraventricular hemorrhage (IVH) growth after spontaneous intracerebral hematoma. The model was developed using a training cohort (N=626) and validated with an independent testing cohort (N=270). Radiomics features and clinical predictors were selected using the least absolute shrinkage and selection operator (LASSO) method and multivariate analysis. The radiomics score (Rad-score) was calculated through linear combination of selected features multiplied by their respective LASSO coefficients. The support vector machine (SVM) method was used to construct the model. IVH growth was experienced by 13.4% and 13.7% of patients in the training and testing cohorts, respectively. The Rad-score was associated with severe IVH and poor outcome. Independent predictors of IVH growth included hypercholesterolemia (odds ratio [OR], 0.12 [95%CI, 0.02-0.90]; p=0.039), baseline Graeb score (OR, 1.26 [95%CI, 1.16-1.36]; p<0.001), time to initial CT (OR, 0.70 [95%CI, 0.58-0.86]; p<0.001), international normalized ratio (OR, 4.27 [95%CI, 1.40, 13.0]; p=0.011), and Rad-score (OR, 2.3 [95%CI, 1.6-3.3]; p<0.001). In the training cohort, the model achieved an AUC of 0.78, sensitivity of 0.83, and specificity of 0.66. In the testing cohort, AUC, sensitivity, and specificity were 0.71, 0.81, and 0.64, respectively. This radiomics-clinical model thus has the potential to predict IVH growth.

Characteristics of Renal Function in Patients Diagnosed With COVID-19: An Observational Study.

Objective: The aim of the study was to analyze the characteristics of renal function in patients diagnosed with COVID-19. Methods: In this retrospective, single-center study, we included all confirmed cases of COVID-19 in a tertiary hospital in Guangdong, China from January 20, 2020 to March 20, 2020. Blood and urine laboratory findings related to renal function were summarized, and the estimated glomerular filtration rate (eGFR) and endogenous creatinine clearance (Ccr) were also calculated to assess the renal function. Results: A total of 12 admitted hospital patients were diagnosed with COVID-19, included 3 severe cases, and 9 common cases. Serum creatinine (Scr) was not abnormally elevated in all of the patients, and blood urea nitrogen (BUN) was abnormally elevated in only 25.0% of the patients. However, compared with the recovery period, the patient's Scr and BUN increased significantly in peak of disease (p-scr = 0.002 & p-bun < 0.001). By observing the fluctuations in Scr and BUN from admission to recovery, it was found that the peak of Scr and BUN appeared within the first 14 day of the course of the disease. Urinary microprotein detection indicated that the abnormally elevated rates of urine microalbumin (UMA), α1-microglobulin (A1M), urine immunoglobulin-G (IGU), and urine transferring (TRU) standardized by urinary creatinine in peak of disease were 41.7, 41.7, 50.0, and 16.7%, respectively. The abnormal rates of the calculated eGFR and Ccr were 66.7 and 41.7%. Conclusion: Scr and BUN were generally increased during the course of COVID-19. Detection of urinary microproteins and application of multiple indicators assessment could be helpful for discovering abnormal renal function in patients with COVID-19. However, the evidence is limited due to the small sample size and observational nature. Additional studies, especially large prospective cohort studies, are required to confirm these findings.

Association of IGF1R polymorphisms (rs1546713) with susceptibility to age-related cataract in a Han Chinese population.

AIM: To explore the susceptible association between the insulin-like growth factor-1 receptor (IGF1R) single nucleotide polymorphism (SNP) and age-related cataract (ARC), and investigate the underlying mechanisms in human lens epithelium (HLE) cells. METHODS: Totally 1190 unrelated participants, comprising 690 ARC patients and 500 healthy individuals in Han Chinese population were recruited and genotyped for target SNP. The χ 2-test was used to detect genotypic distribution between the patient and control groups and the logistic regression was performed to adjust the age and gender. Meanwhile, different biological experimental methods, such as cell counting kit 8 (CCK-8) assay, flow cytometry, quantitative real time polymerase chain reaction (Q-PCR) and Western blot, were used to detect cell viability, cell cycle progression and apoptosis in HLE cells or IGF1R knockdown HLE cells. RESULTS: The rs1546713 in IGF1R gene was identified (P=0.046, OR: 1.606, 95%CI: 1.245-2.071), which shown a significant relevance with ARC risk under the dominant model. The results demonstrated that IGF1R knockdown inhibited cell proliferation by inducing cell cycle arrested at S phase and promoting apoptosis. Mechanistically, the cell cycle blocked at S phase was linked with the alterations of cyclin A, cyclin B, cyclin E and P21. The pro-apoptosis function of IGF1R may related with stimulating the activation of Caspase-3 and altering the expression levels of apoptotic proteins, including Bcl-2, Bax and Caspase-3. CONCLUSION: This study first report that IGF1R polymorphisms may affect susceptibility to ARCs in Han Chinese population and provide new clues to understand the pathogenic mechanism of ARCs. Notably, IGF1R is likely a potential target for ARC prevention and treatment.

Analysis of early renal injury in COVID-19 and diagnostic value of multi-index combined detection

ObjectivesThe aim of the study was to analyze the incidence of COVID-19 with early renal injury, and to explore the value of multi-index combined detection in diagnosis of early renal injury in COVID-19. DesignThe study was an observational, descriptive study. SettingThis study was carried out in a tertiary hospital in Guangdong, China. Participants12 patients diagnosed with COVID-19 from January 20, 2020 to February 20, 2020. Primary and secondary outcome measuresThe primary outcome was to evaluate the incidence of early renal injury in COVID-19. In this study, the estimated glomerular filtration rate (eGFR), endogenous creatinine clearance (Ccr) and urine microalbumin / urinary creatinine ratio (UACR) were calculated to assess the incidence of early renal injury. Secondary outcomes were the diagnostic value of urine microalbumin (UMA), 1-microglobulin (A1M), urine immunoglobulin-G (IGU), urine transferring (TRU) alone and in combination in diagnosis of COVID-19 with early renal injury. ResultsWhile all patients had no significant abnormalities in serum creatinine (Scr) and blood urea nitrogen (BUN), the abnormal rates of eGFR, Ccr, and UACR were 66.7%, 41.7%, and 41.7%, respectively. Urinary microprotein detection indicated that the area under curve (AUC) of multi-index combined to diagnose early renal injury in COVID-19 was 0.875, which was higher than UMA (0,813), A1M (0.813), IGU (0.750) and TRU (0.750) alone. Spearman analysis showed that the degree of early renal injury was significantly related to C-reactive protein (CRP) and neutrophil ratio (NER), suggesting that the more severe the infection, the more obvious the early renal injury. Hypokalemia and hyponatremia were common in patients with COVID-19, and there was a correlation with the degree of renal injury. ConclusionsEarly renal injury was common in patients with COVID-19. Combined detection of UMA, A1M, IGU, and TRU was helpful for the diagnosis of early renal injury in COVID-19.

Effects of “Sweat Soaking Method ”on the Content of Genkwanin in Wikstroemia indica and Its Anti-oxidation Ability / 中国药房

OBJECTIVE：To compare the content changes of active/toxic ingredient genkwanin in ethanol extract from Wikstroemia indica before and after processing with “sweat soaking method ”and the effects of processing method on its anti-oxidation ability. METHODS ：HPLC method was adopted to determine the content of genkwanin in W. indica before and after processing with “sweat soaking method ”. The separation was performed on Diamonsil C 18 column with 0.2％ phosphoric acid solution-methanol as mobile phase （gradient elution ）at the flow rate of 1 mL/min. The column temperature was 30 ℃ and detection wavelength was set at 346 nm. The sample size was 20 µL. SD rats were randomly divided into blank group ，W. indica raw product ethanol extract group （317.52 mg/kg，called“raw-product group ”as short ）and W. indica processed product ethanol extract group （317.52 mg/kg，called“processed-product group ”as short ），with 6 rats in each group. Blank group was given constant volume of 1.0％CMC-Na solution intragastrically ，and administration groups were given relevant medicine suspension intragastrically；all of them were given 20 mL/kg，once a day ，for consecutive 14 days. The contents of serum oxidant stress indexes（MDA，CAT，SOD）in rats were determined by ELISA. RESULTS ：The linear range of genkwanin were 0.147-27.360 μg （r＝0.999 9）；RSDs of precision ，reproducibility and stability tests were all lower than 3％ ；average recoveries were 98.64％-98.92％（RSD＜1％，n＝3）. Before and after processing with “sweat soaking method ”，average contents of genkwanin in W. indica were 0.377 6 and 0.234 0 mg/g. Compared with blank group ，the serum content of SOD in raw-product group was increased significantly ，while CAT content was decreased significantly （P＜0.05 or P＜0.01）；the serum content of MDA was decreased significantly in processed-product group ，while SOD content was increased significantly （P＜0.05 or P＜0.01）. MDA content of processed-product group was significantly lower than that of raw-product group ，while SOD content was significantly higher than raw-product group （P＜0.05）. CONCLUSIONS ：After proce ssing with “sweat soaking method ”，the content of genkwanin in W. indica is decreased ，and antioxidant activity is increased .“Sweat soaking method ”processes certain function of “reducing toxicity and increasing efficiency ”.

Comprehensive benefits of agroforestry snail control forests in Eryuan County, Yunnan Province / 中国血吸虫病防治杂志

Objective To investigate the efficiency of various agroforestry systems for snail control in plateau hilly schistosomiasis-endemic areas of Yunnan Province, so as to provide insights into the construction of agroforestry schistosomiasis control projects in plateau hilly regions. Methods The pilot areas of snail control forests with various agroforestry systems were built in snail-breeding farmlands in Eryuan County, Yunnan Province in 2010, and the economic benefits and snail control effect were investigated in 2018. In addition, a fuzzy comprehensive evaluation model was created to screen the agroforestry system with high comprehensive benefits. Results A total of 14 types of pilot areas of snail control forests with various agroforestry systems were built. Economic benefit analysis showed that the“walnut + garlic”pattern had the best economic benefit, with annual economic benefits of 270 000 Yuan/hm2, followed by the“walnut + chili”pattern (annual economic benefits of 120 000 Yuan/hm2) and the “walnut + vegetables”pattern (annual economic benefits of 105 000 Yuan/hm2). No snails were detected in 8 types of the agroforestry systems, including the“walnut + chili”pattern, the“walnut + tobacco”pattern and the“walnut + garlic”pattern; however, there were snail found with various densities in other types of systems. Fuzzy comprehensive evaluation showed that the“walnut + garlic”pattern had the best comprehensive control effect, followed by the“walnut + chili”pattern and the“walnut + tobacco” pattern, while the pure grassland pattern showed no effect on snail control. Conclusions The agroforestry system is a preferential approach of forestry schistosomiasis control in plateau hilly schistosomiasis-endemic areas, which not only achieves snail control effects, but also promotes economic development and ecological construction in poor hilly areas.

[Prevention of poor incision healing after total knee arthroplasty].

OBJECTIVE: To investigate the causes of poor incision healing after total knee arthroplasty(TKA) and to propose active preventive and therapeutic measures. METHODS: Total 284 patients undergoing unilateral TKA from September 2016 to June 2018 were enrolled in the study and divided into control group and observation group. Firstly, 150 patients with unilateral TKA from September 2016 to June 2017 were retrospectively analyzed and included in the control group. There were 41 males and 109 females, with an average age of(63.5±7.2) years old. The causes of poor incision healing were discussed about patients themselves and surgical techniques. After analyzing, improvement measures were proposed. Total 134 patients with TKA from July 2017 to June 2018 were included in the observation group. There were 36 males and 98 females, with an average age of(62.4±8.9) years old. The patients in the observation group were treated with improved treatment strategies. RESULTS: Nine patients(6%) had poor incision healing in the control group and 1 patient (0.75%) had poor incision healing in the observation group. The incidence of poor incision healing was significantly different between the two groups (χ²=5.750, P<0.01). CONCLUSIONS: In order to prevent the poor incision healing after TKA, perioperative management and the operation techniques including stable, accurate, rapid and clean skills should be improved, leading to reduce the complications of incision and improve the recovery rate of patients.

The Synthesis, Structure, Morphology Characterizations and Evolution Mechanisms of Nanosized Titanium Carbides and Their Further Applications.

It is widely known that the special performances and extensive applications of the nanoscale materials are determined by their as-synthesized structures, especially their growth sizes and morphologies. Hereinto, titanium carbides, which show brilliant comprehensive properties, have attracted considerable attention from researchers. How to give full play to their potentials in the light-weight manufacture, microwave absorption, electromagnetic protection, energy conversion and catalyst areas has been widely studied. In this summarized article, the synthesis methods and mechanisms, corresponding growth morphologies of titanium carbides and their further applications were briefly reviewed and analyzed according to their different morphological dimensions, including one-dimensional nanostructures, two-dimensional nanosheets and three-dimensional nanoparticles. It is believed that through the investigation of the crystal structures, synthesis methods, growth mechanisms, and morphology characterizations of those titanium carbides, new lights could be shed on the regulation and control of the ceramic phase specific morphologies to meet with their excellent properties and applications. In addition, the corresponding development prospects and challenges of titanium carbides with various growth morphologies were also summarized.

Clonal evolution in a chronic neutrophilic leukemia patient.

Objectives and importance: Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R); these mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Clinical presentation: We present a male patient who presented peripheral blood leukocytosis. On the basis of his morphological appearances and molecular findings he was determined to have a diagnosis of chronic neutrophilic leukemia. At a follow-up at 7 months, in addition to the CSF3R c.2373G > A (p.W791*) truncated mutation, another CSF3R mutation appeared as c.1853C > T(p.T618I). Discussion and conclusion: We present the first patient with a diagnosis of chronic neutrophilic leukemia with a c.2373G > A (p.W791*) truncated mutation of CSF3R. These findings elucidate a novel paradigm of CNL pathogenesis and explain how mutations drive the development of the disease. The order of acquisition of CSF3R mutations relative to mutations in epigenetic modifiers and the spliceosome have been determined only in isolated case reports; thus, further work is needed to understand the impact of mutation chronology on the clonal evolution and progression of CNL.

First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity.

PURPOSE: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib). PATIENTS AND METHODS: This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity. RESULTS: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mg N = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, C max was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks. CONCLUSIONS: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.

Surufatinib in Advanced Well-Differentiated Neuroendocrine Tumors: A Multicenter, Single-Arm, Open-Label, Phase Ib/II Trial.

PURPOSE: No antiangiogenic treatment is yet approved for extrapancreatic neuroendocrine tumors (NET). Surufatinib (HMPL-012, previously named sulfatinib) is a small-molecule inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptor 1 and colony-stimulating factor 1 receptor. We conducted a single-arm phase Ib/II study of surufatinib in advanced NETs. PATIENTS AND METHODS: Patients with histologically well-differentiated, low or intermittent grade, inoperable or metastatic NETs were enrolled into a pancreatic or extrapancreatic NET cohort. Patients were treated with surufatinib 300 mg orally, once daily. The primary endpoints were safety and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (version 1.1). RESULTS: Of the 81 patients enrolled, 42 had pancreatic NETs and 39 had extrapancreatic NETs. Most patients had radiologic progression within 1 year prior to enrollment (32 patients in each cohort). In the pancreatic and extrapancreatic NET cohorts, ORRs were 19% [95% confidence intervals (CI), 9-34] and 15% (95% CI, 6-31), disease control rates were 91% (95% CI, 77-97) and 92% (95% CI, 79-98), and median progression-free survival was 21.2 months (95% CI, 15.9-24.8) and 13.4 months (95% CI, 7.6-19.3), respectively. The most common grade ≥3 treatment-related adverse events were hypertension (33%), proteinuria (12%), hyperuricemia (10%), hypertriglyceridemia, and diarrhea (6% for each), and increased alanine aminotransferase (5%). CONCLUSIONS: Surufatinib showed encouraging antitumor activity and manageable toxicities in patients with advanced NETs. Two ongoing phase III studies, validating the efficacy of surufatinib in patients with NETs, will contribute to the clinical evidence.

Melatonin Alleviates Copper Toxicity via Improving Copper Sequestration and ROS Scavenging in Cucumber.

Melatonin plays an important role in stress tolerance in plants. In this study, exogenous melatonin significantly alleviated the dwarf phenotype and inhibited the decrease of plant fresh weight induced by excess copper (Cu2+). Our results indicated that melatonin alleviated Cu2+ toxicity by improving Cu2+ sequestration, carbon metabolism and ROS (reactive oxygen species) scavenging, rather than by influencing the Cu2+ uptake under excess Cu2+ conditions. Transcriptome analysis showed that melatonin broadly altered gene expression under Cu2+ stress. Melatonin increased the levels of glutathione and phytochelatin to chelate excess Cu2+ and promoted cell wall trapping, thus keeping more Cu2+ in the cell wall and vacuole. Melatonin inhibited ROS production and enhanced antioxidant systems at the transcriptional level and enzyme activities, thus building a line of defense in response to excess Cu2+. The distribution of nutrient elements was recovered by melatonin which was disturbed by Cu2+. In addition, melatonin activated carbon metabolism, especially glycolysis and the pentose phosphate pathway, to generate more ATP, an intermediate for biosynthesis. Taken together, melatonin alleviated Cu2+ toxicity in cucumber via multiple mechanisms. These results will help to resolve the toxic effects of Cu2+ stress on plant growth and development. These results can be used for new strategies to solve problems associated with Cu2+ stress.