[Dosimetric Impact of Titanium Alloy Implant in Spinal IMRT Plan].

The purpose of this study is to establish and apply a correction method for titanium alloy implant in spinal IMRT plan, a corrected CT-density table was revised from normal CT-density table to include the density of titanium alloy implant. Dose distribution after and before correction were calculated and compared to evaluate the dose deviation. Plans were also copied to a spinal cancer simulation phantom. A titanium alloy fixation system for spine was implanted in this phantom. Plans were recalculated and compared with the measurement result. The result of this study shows that the max dose of spinal cord showed significant difference after correction, and the deviation between calculation results and measurement results was reduced after correction. The method for expanding the range CT-density table, which means that the density of titanium alloy was included, can reduce the error in calculation.

Allometric Characteristics of Rice Seedlings under Different Transplanted Hills and Row Spacing: Impacts on Nitrogen Use Efficiency and Yield.

The number of seedlings per hill and the configuration of plant row spacing are important management measures to improve rice yield. In the present study, we evaluated the impact of various seedlings per hill (1, 3, 6, and 9 seedlings hill-1) under four different rice verities (two conventional rice, two hybrid rice) on allometric characteristics, nitrogen use efficiency (NUE) and yield in 2020 at early and late season. Results showed that compared with nine seedlings per hill (wide row spacing), the number of effective panicles, yield, grain biomass allocation, grain-to-leaf ratio, grain nitrogen accumulation, nitrogen dry matter production efficiency (NDMPE), N harvest index (NHI) of 1 seedling per hill increased by 21.8%, 10.91%, 10.5%, 32.25%, 17.03%, 9.67%, 6.5%, respectively. With the increase of seedlings per hill and the expansion of row spacing, stem biomass (SB) and reproductive biomass (RB) increased with the increase of above-ground biomass, mainly showing the relationship of isometric growth. Leaf biomass (LB) increased with above-ground biomass, mainly showing the relationship of allometric growth. The results suggested that under the same basic seedlings, transplanting 1 seedling per hill and dense planting was the most beneficial to improve rice yield.

Analysis of Risk Factors of Coagulation Dysfunction and Hemorrhage in Newly Diagnosed Hyperleukocytic Acute Myeloma Leukemia.

Purpose: To explore whether and why abnormal coagulation function and hemorrhage can appear in patients with hyperleukocytic acute myeloid leukemia (HAML). Method: We retrospectively reviewed the charts of 724 acute myeloid leukemia (AML) patients admitted with a white blood cell count of >100 × 109/L between 2010 and 2019 in order to analyze the coagulation index of patients with HAML and explore the correlation of abnormal coagulation. Result: Prothrombin time (PT) was extended in group HAML compared with group non-HAML. Respiratory failure, intracranial hemorrhage, and infection were more common in the HAML group. Among the 76 HAML patients, there were 33 patients who had ≥3 abnormal items of coagulation index, and 51.5% of them had level 2 hemorrhage which was more than level 0 hemorrhage, and the difference is statistically significant (P < 0.01). Similarly, we can discover that 40.9% of patients with 2 abnormal items had level 2 hemorrhage in contrast to 0 abnormal items. The use of hydroxyurea had a significant effect on PT and D-dimer (DD). Survival analysis by the Kaplan-Meier method showed that there were statistically significant differences in white blood cell (WBC) count＞200 × 109//L and DD. Abnormal PT is associated with WBC count＞200 × 109//L, and abnormal activated partial thromboplastin time (APTT) is associated with HLA-DR mutation. Infection and respiratory failure were independent influencing factors for the coagulation of patients. Conclusion: DD had a marked effect on the survival rate. Infection and respiratory failure were independent influencing factors for the coagulation of patients.

Assessment of infection in newly diagnosed multiple myeloma patients: risk factors and main characteristics.

BACKGROUND: Infection is a leading cause of morbidity and death in patients with multiple myeloma (MM). The increased susceptibility to infection is complicated and multifactorial. However, no studies have explored the spectrum and risk factors of infections in newly diagnosed MM patients at the first admission. This cross-sectional study aimed to provide ideas for the assessment, prevention and treatment of infection in newly diagnosed MM patients when admitted for the first time. METHODS: Retrospectively, the data from electronic medical records for 161 patients newly diagnosed with MM from May 2013 to December 2018 were analysed. All the information was collected at the time of admission, and the patients had received no antineoplastic therapy previously. Independent risk factors of infection in multiple myeloma were determined by univariate and multivariate analysis. RESULTS: Newly diagnosed patients with MM were highly susceptible to viruses (43.9%), especially Epstein-Barr virus (EBV) (24.4%) and hepatitis B virus (HBV) (17.1%). Advanced stage (ISS stage III, P = 0.040), more severe anaemia (Hb < 90 g/L, P = 0.044) and elevated CRP (> 10 mg/L, P = 0.006) were independent risk factors for infection. Moreover, infections represented a major survival threat to patients with newly diagnosed MM (P = 0.033), and the existence of risk factors for infection was significantly correlated with poor prognosis (P = 0.011), especially ISS stage III (P = 0.008) and lower haemoglobin level (P = 0.039). CONCLUSIONS: Newly diagnosed MM patients are highly susceptible to viruses. Advanced ISS stage, more severe anaemia and the elevation of CRP are independent risk factors of infection, which also have a strong impact on prognosis. Our results suggest that viral infection should be taken into account if antibacterial drugs are not effective, and the prevention of infection and improvement of prognosis should be paid more attention in newly diagnosed patents with advanced stage and more severe anaemia.

The novel thioredoxin reductase inhibitor A-Z2 triggers intrinsic apoptosis and shows efficacy in the treatment of acute myeloid leukemia.

Chemoresistance and high incidence of relapse in acute myeloid leukemia (AML) patients are associated with thioredoxin (Trx) overexpression. Thus, targeting the Trx system has emerged as a promising approach to treating AML. Both arsenicals and azelaic acid (AZA) are thioredoxin reductase (TrxR) inhibitors and possess antileukemic effects. In this study, to exploit agents with higher potency and lower toxicity, we got some organic arsenicals and further synthesized a series of targeted compounds by binding AZA to organic arsenicals, and then screened the most effective one, N-(4-(1, 3, 2-dithiarsinan-2-yl) phenyl)-azelamide (A-Z2). A-Z2 showed a stronger inhibitory effect against TrxR activity and in AML cell lines than did AZA or arsenicals. Additionally, A-Z2 was less toxic to healthy cells compared with traditional chemotherapeutic drugs. A-Z2 induces apoptosis by collapsing of mitochondrial membrane potential, reducing ATP level, releasing of cytochrome c and TNF-α, activating of caspase 9, 8 and 3. Analysis of the mechanism revealed that A-Z2 activates the intrinsic apoptotic pathway by directly selectively targeting TrxR/Trx and indirectly inhibiting NF-κB. A-Z2's better efficacy and safety profile against arsenicals and azelaic acid were also evident in vivo. A-Z2 had better plasma stability and biological activity in rats. A-Z2-treated mice displayed significant symptom relief and prolonged survival in a patient-derived xenograft (PDX) AML model. Herein, our study provides a novel antitumor candidate and approach for treating AML.

Antiproliferative and Immunoregulatory Effects of Azelaic Acid Against Acute Myeloid Leukemia via the Activation of Notch Signaling Pathway.

Acute myeloid leukemia (AML) is a common type of hematological malignancy that can progress rapidly. AML has a poor prognosis and a high incidence of relapse due to therapeutic resistance. Azelaic acid (AZA), a small molecular compound is known to exhibit antitumor effect on various tumor cells. This study aimed to evaluate the antiproliferative and immunoregulatory effects of AZA against AMLviathe activation of the notch signaling pathway. We found that AZA can inhibit the proliferation of AML cells. In addition, laser confocal microscopy showed AZA-treated AML cells began to swelling and undergo cytoplasmic vacuolization. Importantly, AZA promoted the proliferation of NK and T cells and increased the secretion of TNF-αand IFN-γ. AZA also increased the expression levels of CD107a and TRAIL in NK cells, and CD25 and CD69 in T cells to influence their activation and cytotoxic ability. AZA-treated NK cells can kill AML cells more efficiently at the single-cell level as observed under the microfluidic chips. Further mechanistic analysis using protein mass spectrometry analysis and Notch signaling reporter assay demonstrated that Notch1and Notch2 were up-regulated and the Notch signaling pathway was activated. Moreover, combining AZA with the Notch inhibitor, RO4929097, decreased the expression of Notch1and Notch2, and downstream HES1 and HEY1, which rendered AML cells insensitive to AZA-induced apoptosis and alleviated AZA-mediated cytotoxicity in AML. In vivo, AZA relieved the leukemic spleen infiltration and extended the survival. The percentage of CD3-CD56+NK cells and CD4+CD8+T cells as well as the secretion of cytotoxic cytokines was increased after the treatment of AZA. The overall findings reveal that AZA is a potential Notch agonist against AML in activating the Notch signaling pathway.

Insight into the glycosylation and hydrolysis kinetics of alpha-glucosidase in the synthesis of glycosides.

α-Glucosidase, Agl2, from Xanthomonas campestris was successfully overexpressed in Escherichia coli BL21(DE3) cells and purified with Ni columns. The enzyme exhibits glycosylation abilities towards a wide range of phenolic substrates, including phenol, vanillin, and ethyl vanillin, with maltose as the glycosyl donor. The catalytic properties of the purified enzyme were further investigated. It was observed that the synthesized glycosides started to degrade with prolonged catalytic time, giving an "n"-shaped kinetic profile. To understand such catalytic behavior, the Agl2-catalyzed glycosylation process was investigated kinetically. Based on the obtained parameters, it was concluded that although the substrate conversions are thermodynamically restricted in a batch system, the glycosylation efficiency can be kinetically controlled by the glycosylation/hydrolysis selectivity. Glucose was produced by both glycosylation and hydrolysis, significantly impacting the glycosylation efficiency. This study provides a mechanistic understanding of the α-glucosidase-catalyzed glycosylation process in a water-based system. The developed kinetic model was successful in explaining and analyzing the catalytic process. It is suggested that when α-glucosidase is employed for glycosylation in a water-enriched environment, the catalytic efficiency is mainly impacted by the enzyme's glycosylation/hydrolysis selectivity and glucose content in the catalytic environment.

Optimization of whole-cell biotransformation for scale-up production of α-arbutin from hydroquinone by the use of recombinant Escherichia coli.

α-Arbutin is an effective skin-whitening cosmetic ingredient and hyperpigmentation therapy agent. It can be synthesized by one-step enzymatic glycosylation of hydroquinone (HQ), but limited by the low yield. Amylosucrase (Amy-1) from Xanthomonas campestris pv. campestris 8004 was recently identified with high HQ glycosylation activity. In this study, whole-cell transformation by Amy-1 was optimized and process scale-up was evaluated in 5000-L reactor. In comparison with purified Amy-1, whole-cell catalyst of recombinant E. coli displays better tolerance against inhibitors (oxidized products of HQ) and requires lower molar ratio of sucrose and HQ to reach high conversion rate (> 99%). Excess accumulation of glucose (0.6-1.0 M) derived from sucrose hydrolysis inhibits HQ glycosylation rate by 46-60%, which suggests the importance of balancing HQ glycosylation rate and sucrose hydrolysis rate by adjusting the activity of whole-cell catalyst and HQ-fed rate. Using optimal conditions, 540 mM of final concentration and 95% of molar conversion rate were obtained within 13-18 h in laboratory scale. For industrial scale-up production, 398 mM and 375 mM of final concentration with high conversion rates (~ 95%) were obtained in 3500-L and 4000-L of reaction volume, respectively. These yields and productivities (4.5-4.9 kg kL-1 h-1) were the highest by comparing to the best we known. Hence, high-yield production of α-arbutin by batch-feeding whole-cell biotransformation was successfully achieved in the 5000-L reaction scale.

Characterization of Glucokinase Catalysis from a Pseudo-Dimeric View.

Glucose phosphorylation by glucokinase exhibits a sigmoidal dependency on substrate concentration regardless of its simple structure. Dimorph mechanism suggested the existence of two enzymatic states with different catalytic properties, which has been shown to be plausible by structural analysis. However, the dimorph mechanism gives rise to a complicated or non-explicit non-closed mathematical form. It is neither feasible to apply the dimorph mechanism in effector characterizations. To improve the area of glucokinase study with stronger theoretical support and less complication in computation, we proposed the investigation of the enzyme from a pseudo-dimeric angle. The proposed mechanism started from the idealization of two monomeric glucokinase as a dimeric complex, which significantly simplified the glucose phosphorylation kinetics, while the differences in enzyme reconfiguration caused by variable substrates and effectors have been successfully characterized. The study presented a simpler and more reliable way in studying the properties of glucokinase and its effectors, providing guidelines of effector developments for hyperglycemia and hypoglycemia treatment.

A real-time respiration position based passive breath gating equipment for gated radiotherapy: a preclinical evaluation.

PURPOSE: To develop a passive gating system incorporating with the real-time position management (RPM) system for the gated radiotherapy. METHODS: Passive breath gating (PBG) equipment, which consists of a breath-hold valve, a controller mechanism, a mouthpiece kit, and a supporting frame, was designed. A commercial real-time positioning management system was implemented to synchronize the target motion and radiation delivery on a linear accelerator with the patient's breathing cycle. The respiratory related target motion was investigated by using the RPM system for correlating the external markers with the internal target motion while using PBG for passively blocking patient's breathing. Six patients were enrolled in the preclinical feasibility and efficiency study of the PBG system. RESULTS: PBG equipment was designed and fabricated. The PBG can be manually triggered or released to block or unblock patient's breathing. A clinical workflow was outlined to integrate the PBG with the RPM system. After implementing the RPM based PBG system, the breath-hold period can be prolonged to 15-25 s and the treatment delivery efficiency for each field can be improved by 200%-400%. The results from the six patients showed that the diaphragm motion caused by respiration was reduced to less than 3 mm and the position of the diaphragm was reproducible for difference gating periods. CONCLUSIONS: A RPM based PBG system was developed and implemented. With the new gating system, the patient's breath-hold time can be extended and a significant improvement in the treatment delivery efficiency can also be achieved.