Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes.

PURPOSE: The synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar-indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML). METHODS: In this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR4), molecular response 4.5 (MR4.5), progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: The median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR4 rates were similar in both arms. However, the 12-month cumulative rates of MR4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups. CONCLUSION: The results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

Correction: Chen et al. Multifunctional Injectable Hydrogel Loaded with Cerium-Containing Bioactive Glass Nanoparticles for Diabetic Wound Healing. Biomolecules 2021, 11, 702.

The authors would like to replace Figure 4A of the following published paper [...].

Hereditary hemorrhagic telangiectasia involving portal venous system: A case report and review of the literature.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder with an incidence of approximately 1 in 5000 in the general population. It is characterized by vasodilation, which affects specific organs, such as the skin, mucous membranes, brain, lungs, gastrointestinal tract, liver, and others. However, HHT rarely involves the portal venous system to cause serious clinical complications. CASE SUMMARY: A 68-year-old woman was admitted to the emergency department due to four consecutive days of abdominal pain and bloody stool and was subsequently diagnosed with HHT. Computed tomography angiography confirmed the presence of an arteriovenous fistula (AVFs). Considering this specific manifestation, whole exome sequencing was performed. After a comprehensive evaluation, a selective superior mesenteric artery embolization was prioritized to avoid intestinal ischemia. The postoperative symptoms of the patient were quickly relieved. Unfortunately, two months post-procedure the patient died from intestinal necrosis and abdominal infection related to remaining AVFs. CONCLUSION: For patients with diffuse superior mesenteric AVFs, selective mesenteric arterial embolization may lead to positive short-term outcomes.

Constructing quasi-layered and self-hole doped SnSe oriented films to achieve excellent thermoelectric power factor and output power density.

Thermoelectric (TE) technology can achieve the mutual conversion between electric energy and waste heat, and it has exhibited great prospects in multifunctional energy applications to alleviate the energy crisis. In the recent decade, SnSe has been explored widely because of its potentially high energy harvesting efficiency, green nature, and low cost. However, the relatively poor power factor (PF) derived from the intrinsic low carrier concentration (∼1017 cm-3) limits the output power density of the stoichiometric SnSe devices. Therefore, the advancement of novel optimization strategies for controlling carrier concentration is of utmost importance. Besides, compared with 3D bulks, 2D thin films are more compatible with modern semiconductor technology and have unique advantages in the construction and application of TE micro- and nano-devices. In this study, post-selenization technology were applied to increase the carrier concentration of the a-axis oriented SnSe epitaxial films utilizing the charge transfer and self-hole doped effects. The quasi-layered and self-hole doped films exhibited a high power factor of ∼5.9 µW cm-1 K-2 at 600 K along the in-plane direction when the carrier concentration is enhanced to ∼1018 cm-3 by increasing the selenization time to ∼20 min. The TE generator composed of four P-type film legs demonstrated the ultrahigh maximum power density of ∼83, ∼838 µW cm-2 at the temperature difference of ∼50 and ∼90 K, respectively. Post-selenization can effectively optimize the carrier concentration of SnSe-based materials, which is also feasible to other anion deficient TE films.

Arginase from Priestia megaterium and the Effects of CMCS Conjugation on Its Enzymological Properties.

Arginase has shown promising potential in treating cancers by arginine deprivation therapy; however, low enzymatic activity and stability of arginase are impeding its development. This study was aimed to improve the enzymological properties of a marine bacterial arginase by carboxymethyl chitosan (CMCS) conjugation. An arginase producing marine bacterium Priestia megaterium strain P6 was isolated and identified. The novel arginase PMA from the strain was heterologously expressed, purified, and then conjugated to CMCS by ionic gelation with calcium chloride as the crosslinking agent. Enzymological properties of both PMA and CMCS-PMA conjugate were determined. The optimum temperature for PMA and CMCS-PMA at pH 7 were 60 °C and 55 °C, respectively. The optimum pH for PMA and CMCS-PMA at 37 °C were pH 10 and 9, respectively. CMCS-PMA showed higher thermostability than PMA over 55-70 °C and higher pH stability over pH 4-11 with the highest pH stability at pH 7. At 37 °C and pH of 7, i.e., around the human blood temperature and pH, CMCS-PMA was higher than the free PMA in enzymatic activity and stability by 24% and 21%, respectively. CMCS conjugation not only changed the optimum temperature, optimum pH, and enzymatic activity of PMA, but also improved its pH stability and temperature stability, and thus made it more favorable for medical application.

Efficacy of Xiyanping in the Treatment of Elderly Patients with Chronic Obstructive Pulmonary Disease and Its Effect on the Expression of GDF-15 and HIF-1α in Serum.

Background: COPD is a chronic respiratory disease with a long course and recurrent characteristics. According to relevant statistics, the global incidence of COPD is more than 30%, which seriously affects the life of patients and endangers their health. Objective: To observe the curative effect of Xiyanping in elderly patients with COPD and its influence on the expressions of growth differentiation GDF-15 and HIF-1α in serum. Methods: From August 2019 to December 2021, 86 elderly patients with acute exacerbation of COPD were admitted to our hospital. As the research objects, they were divided into the control group (n = 43) and the observation group (n = 43) randomly. The control group received the conventional treatment, while the observation group got Xiyanping on the basis of the control group. The differences in the duration of antibiotic use, expectoration, hospital stays, adverse reactions and serum-related factors, blood routine, pulmonary function, airway hyperreactivity index, COPD assessment test (CAT) score, and Borg score were made a comparison between them. Results: On the 3rd and 7th days after being treated, the sputum excretion in them was higher than before, but on the 3rd day of treatment, the sputum excretion in the observation group was higher than that in the control group, while on the 7th day of treatment, the sputum excretion was lower than that in the control group with statistically significant differences (P < 0.05). Before treatment, the serum-related factors and blood routine indexes between them were similar (P > 0.05). After treatment, GDF-15, HIF-1α, CXCL12, TNF-α, IL-8, TGF-ß, WBC, and NEU in them were significantly lower than before, and the values in the observation group were significantly lower than those in the control group with statistically significant differences (P < 0.05). There was no difference in the related indexes of pulmonary function and airway hyperreactivity between them before treatment. After being treated, FEV1, FVC, and FEV1/FVC in them were significantly higher than those before treatment. The airway resistance and lung compliance of the two groups at exhalation and inspiration were significantly lower than before, and the values in the observation group were significantly lower than those in the control group (P < 0.05). There was no difference in CAT and Borg scores between them before treatment. After treatment, the CAT score and Borg score of these patients were significantly lower than those before treatment, and the value of the observation group was significantly lower than that of the control group (P < 0.05). The duration of antibiotic use and length of stay in the observation group were significantly shorter than those of the control group, while the incidence of adverse reactions was not statistically significantly different compared with the control group (P > 0.05). Conclusion: Xiyanping can improve pulmonary function of elderly patients with acute exacerbation of COPD, reduce the response of airway hyperreactivity, and promote the excretion of sputum.

Recent strategies for improving hemocompatibility and endothelialization of cardiovascular devices and inhibition of intimal hyperplasia.

Cardiovascular diseases have become one of the leading causes of mortality worldwide. Stents and artificial grafts have been used to treat cardiovascular diseases. Thrombosis and restenosis seriously impact the clinical outcome of stents and artificial vascular grafts. For the purpose of antithrombosis and anti-restenosis, numerous strategies have been developed to construct highly hemocompatible surfaces, enhance endothelialization, and inhibit intimal hyperplasia. Rapid endothelialization and inhibited intimal hyperplasia play an important role in artery repair after stent implantation and coronary artery bypass graft surgery. This review focuses on the recently developed strategies for improving the hemocompatibility and endothelialization of cardiovascular devices. We also introduce drug, gene and RNA delivery technologies for inhibiting intimal hyperplasia. The challenges and future perspectives about promoting endothelialization are also briefly discussed with the hope to help inspire further innovations.

Diagnostic and prognostic value of genomic instability-derived long non-coding RNA signature of endometrial cancer.

OBJECTIVE: To investigate whether genomic instability (GI)-derived long non-coding RNAs (lncRNAs) have a prognostic impact on the patients with endometrial cancer. MATERIAL AND METHODS: Patients with Uterine Corpus Endometrial Carcinoma (UCEC) were selected from The Cancer Genome Atlas (TCGA) database. Systematic bioinformatics analyses were performed, including Pearson correlations, GO and KEGG enrichment analysis, bivariate and multiple logistic regression analysis, and Kaplan-Meier (KM) method. RESULTS: A total of 552 UCEC samples were included in the study. The differentially expressed lncRNAs (DELs) were identified, including 79 down-regulated lncRNAs and 31 up-regulated lncRNAs. Bivariate logistic regression analysis showed that 19 GI-derived lncRNAs were prognostic factors. By further multivariate logistic regression analysis, AC005256.1 (estimated coefficient = -0.474), AC026336.3 (estimated coefficient = -0.030), AL161618.1 (estimated coefficient = -1.661), and BX322234.1 (estimated coefficient = 1.511) were used to construct a prognostic risk model. In the train set and test set, the risk model was shown to have both a high prognostic and a diagnostic value. CONCLUSION: We developed a novel GI-derived 4-lncRNA signature for the diagnosis and prognosis of patients with endometrial cancer. These findings offered a novel perspective in the clinical management of endometrial cancer.

Comparison of Resilience Among Healthcare Workers During the COVID-19 Pandemics: A Multinational Cross-Sectional Survey in Southeast Asian Jurisdictions.

Objectives: To examine the level of resilience among the frontline healthcare workers (HCWs) in four different Southeast Asian jurisdictions and identify the potential factors that may enhance healthcare workers resilience. Methods: An online cross-sectional survey was carried out among 3,048 eligible healthcare workers in Hong Kong, Nepal, Vietnam, and Taiwan from May 2021 to July 2022, and information on individual resilience, socio-demographic characteristics, organizational supports, and personal exposures were collected. A binary logistic regression model was used to identify the factors that were associated with a high resilience level. Results: The resilience score was the highest among healthcare workers of Vietnam, followed by Taiwan and Hong Kong, with Nepal scoring the lowest. Participants with old age, part-time work, higher education level, more satisfaction with workplace policy, better organizational supports, and fewer COVID-specific worries were associated with higher resilience. Healthcare workers who were satisfied with the overall organizational policy support had an OR of 1.48 (95% CI: 1.25-1.76) for a high resilience level. Conclusion: Implementing satisfying organizational policies and establishing supportive work environments for frontline healthcare workers can increase individual resilience and organizational stability.

Systematic chemical characterization of Xiexin decoctions using high performance liquid chromatography coupled with electrospray ionization mass spectrometry.

Xiexin decoctions (XXDs) display beneficial anti-inflammatory and anti-diabetic effects, which raises interests on this group of formulae for broad clinical applications. However, there was no report about systematic analysis of XXDs to elucidate the constitution of chemical components, which hampers further investigations on the therapeutic values of XXDs. In this work, crude herbs were extracted and prepared to obtain the XXDs for systemic analysis on their chemical compositions, according to the information described in the ancient Zhang Zhongjing's herbal formulae. LC-MS analysis of five XXDs was carried out to facilitate recognition of the source herbs for compounds in the mixture. A total number of 93 compounds were identified through our methods and their chemical classes encompassed five major groups, including protoberberine alkaloids, flavonoids, stilbenes, anthraquinones and saponins. Our current work provided important information about material basis for pharmacological studies on XXDs and would help shed light on relationships between chemical compositions and therapeutic effects.

Multifunctional Injectable Hydrogel Loaded with Cerium-Containing Bioactive Glass Nanoparticles for Diabetic Wound Healing.

Diabetic foot wound healing is a major clinical problem due to impaired angiogenesis and bacterial infection. Therefore, an effective regenerative dressing is desiderated with the function of promoting revascularization and anti-bacteria. Herein, a multifunctional injectable composite hydrogel was prepared by incorporation of the cerium-containing bioactive glass (Ce-BG) into Gelatin methacryloyl (GelMA) hydrogel. The Ce-BG was synthesized by combining sol-gel method with template method, which maintained spherical shape, chemical structure and phase constitution of bioactive glass (BG). The Ce-BG/GelMA hydrogels had good cytocompatibility, promoted endothelial cells migration and tube formation by releasing Si ion. In vitro antibacterial tests showed that 5 mol % CeO2-containing bioactive glass/GelMA (5/G) composite hydrogel exhibited excellent antibacterial properties. In vivo study demonstrated that the 5/G hydrogel could significantly improve wound healing in diabetic rats by accelerating the formation of granulation tissue, collagen deposition and angiogenesis. All in all, these results indicate that the 5/G hydrogel could enhance diabetic wound healing. Therefore, the development of multifunctional materials with antibacterial and angiogenic functions is of great significance to promote the repair of diabetic wound healing.

Characterization of the chemical constituents of Jie-Geng-Tang and the metabolites in the serums and lungs of mice after oral administration by LC-Q-TOF-MS.

Jie-Geng-Tang (JGT), a traditional formula, is employed in the treatment of sore throat and cough and comprises Platycodonis Radix and Glycyrrhizae Radix et Rhizoma in the ratio 1 : 2. Our previous study demonstrated that JGT protected mice from S. aureus-induced acute lung injury (ALI). Five constituents of JGT showed antibacterial activities against S. aureus in vitro. However, the potential effective constituents of JGT in vivo were still unclear. In this study, the chemical constituents of JGT were identified by liquid chromatography with quadrupole time-of-flight spectrometry (LC-Q-TOF-MS). A total of 96 constituents were identified or assumed, including seven organic acids, 45 flavonoids, 36 triterpene saponins, and eight compounds of other types. The structures of 31 of the constituents were confirmed by comparing them with corresponding authentic standards. Moreover, 15 prototypes and 49 metabolites were deduced in the serums of mice, 24 prototypes and 47 metabolites were deduced in the lungs of mice after the oral administration of JGT. Three types of constituents, namely organic acids, flavonoids, and triterpene saponins, could be absorbed into the blood. Moreover, flavonoids and triterpene saponins were more likely distributed in the lung than in the blood. To the best of our knowledge, this is the first report on the systematic metabolites profile of JGT in vivo. The results reported were beneficial to the elucidation of the effective material basis of JGT.

miR-330 alleviates dextran sodium sulfate-induced ulcerative colitis through targeting IRAK1 in rats.

Ulcerative colitis (UC) is a chronic multifactorial inflammatory bowel disease that severely impairs patients' life quality. microRNAs (miRNAs) have been reported to exhibit potential therapeutic effects in the management of UC. With the aim to investigate the regulatory effects of miR-330 on UC-related colon tissue damage and inflammation, a rat model of experimental colitis was established by oral administration of dextran sodium sulfate (DSS). DSS-treated rats showed mucosal damage, colonic inflammation, and elevated myeloperoxidase activity compared with the healthy controls. Dual-luciferase reporter assay confirmed the binding of interleukin-1 receptor-associated kinase 1 (IRAK1) and miR-330. Subsequently, rats were intracolonically injected with miR-330 argomir with/without administration of IRAK1 during DSS treatment. The miR-330 overexpression reduced DSS-induced colonic injury and the production of proinflammatory cytokines. The level of IRAK1 was negatively regulated by the expression of miR-330. IRAK1 overexpression abolished the protective effect of miR-330 on DSS-induced colonic inflammation and mucosal injury in rats. In conclusion, we clarify the role of miR-330 in pathogenesis of UC, suggesting miR-330 alleviated DSS-induced colitis by downregulating IRAK1, shedding lights on miR-330 as a therapeutic candidate for UC treatment.

Expression of the epigenetic H3K27me3 modifier genes KDM6A and EZH2 in patients with upper tract urothelial carcinoma.

The development of upper tract urothelial carcinoma (UTUC) has been associated with the ingestion of aristolochic acid (AA) in Chinese herbs. The tumors are more malignant and patients have a worse prognosis in China compared with that in Western countries. Recently, whole-genome and exome sequencing of AA-associated UTUCs found that the most frequently mutated gene was lysine demethylase 6A (KDM6A). However, its biological role and clinical significance have not yet been defined in patients with UTUC in China. A total of 108 surgically resected UTUC samples were obtained. Using immunohistochemistry, the protein expression level of KDM6A in the tumors was investigated together with the clinical and pathological characteristics of the patients, including survival times. In the present study, the expression level of KDM6A was significantly lower in UTUC specimens compared with that in samples from the normal urothelium. Lower KDM6A expression was also found to be significantly associated with a higher tumor grade and shorter cancer-specific and disease-free survival times (P=0.023 and P=0.033, respectively). In addition, using immunohistochemical analysis, no positive association was found between KDM6A expression and the expression of H3K27me3 or histone-lysine N-methyltransferase EZH2, a histone methyltransferase that generates H3K27me3. The results of the present study indicated that decreased KDM6A expression level was significantly associated with tumor grade and decreased survival time in UTUC, suggesting that KDM6A expression could be used as a prognostic marker in patients with UTUC in China.

[Analysis of chemical constituents in Shenmai Injection by LC-Q-TOF-MS and LC-IT-MS].

The chemical constituents in Shenmai Injection(SMI) were qualitatively analyzed by using liquid chromatography/quadrupole time-of-flight mass spectrometry(LC-Q-TOF-MS) and liquid chromatography-ion trap-mass spectrometry(LC-IT-MS). The analysis was performed on an Agilent Zorbax SB-C_(18)(4.6 mm×250 mm, 5 µm) and gradient elution was carried out with 0.05% formic acid solution-acetonitrile as mobile phase at a flow rate of 0.6 mL·min~(-1) and a column temperature of 30 ℃. Mass spectrometry data of the components in SMI were collected in negative ion mode. The structures of components were speculated and identified by analyzing mass spectrometry data, comparing with standards, and referring to related literature. A total of 64 components in SMI were estimated, and the structures were confirmed in 16 of them by comparison with standards. Fifty-six compounds derived from Ginseng Radix et Rhizoma Rubra included 34 protopanaxadiol ginsenosides, 19 protopanaxatriol ginsenosides, 1 oleanane ginsenosides and 2 other glycosides. Eight compounds derived from Ophiopogonis Radix included 7 steroidal saponins, and 1 monoterpene glycoside. The results of this study would provide an important theoretical basis for the improvement of the quality control standards and the discovery of effective constituents in SMI.

Identification of constituents in Gui-Zhi-Jia-Ge-Gen-Tang by LC-IT-MS combined with LC-Q-TOF-MS and elucidation of their metabolic networks in rat plasma after oral administration.

Gui-Zhi-Jia-Ge-Gen-Tang (GZJGGT) is a traditional Chinese medicine (TCM) prescription commonly used to treat cervical spondylopathy, scapulohumeral periarthritis, etc. Though it is widely applied in clinical practice, the effective constituents of GZJGGT remain unclear. This was the first report on the identification of the chemical constituents from GZJGGT in vitro and in vivo using LC-IT-MS combined with LC-Q-TOF-MS. A total of 141 constituents were detected in GZJGGT, and 77 were identified. These compounds mainly included flavonoid glycosides, triterpene saponins, monoterpene glycosides, puerosides, and organic acids. Among them, 12 compounds were unequivocally identified in comparison with reference substances. Additionally, a diagnostic base peak ion filtering strategy for rapid classification of flavonoid O-glycosides and C-glycosides was proposed. After gastrointestinal administration of GZJGGT to rats, 45 prototypes and 48 metabolites in rat plasma were speculated. In addition, the metabolic profile of GZJGGT was portrayed to understand interrelationship between metabolites.

Rapid discovery and identification of the anti-inflammatory constituents in Zhi-Shi-Zhi-Zi-Chi-Tang.

The anti-inflammatory active ingredients of Zhi-Shi-Zhi-Zi-Chi-Tang (ZSZZCT), a traditional Chinese medicine formula, were predicted and identified using an approach based on activity index, LC-MS, semi-preparative LC and NMR. Firstly, the whole extract of ZSZZCT was analyzed using liquid chromatography-quadrupole time of flight-mass spectrometry (LC-Q-TOF-MS) and liquid chromatography - ion trap mass spectrometry (LC-IT-MS), 79 constituents were detected and 39 constituents were identified unambiguously or tentatively. Subsequently, the whole extract of the formula was separated into multiple components and the activity index method was used to calculate index values of the 79 constituents by integrating the chemical and pharmacological information of multiple components. Four polymethoxyl flavones were predicted as the major active constituents according to the activity index values. Furthermore, three polymethoxyl flavones were prepared using the strategy with semi-preparative LC guided by LC-MS, and their anti-inflammatory activities were validated. The results show that three polymethoxyl flavones with higher positive index values, i.e., 3, 5, 6, 7, 8, 3', 4'-heptamethoxyflavone, 3-hydroxynobiletein and tangeretin had significant anti-inflammatory effects. In conclusion, the predicted results indicated that the activity index method is feasible for the accurate prediction of active constituents in TCM formulae.

Acute restraint stress triggers progesterone withdrawal and endometrial breakdown and shedding through corticosterone stimulation in mouse menstrual-like model.

Stress impacts the reproductive axis at the level of the hypothalamus and the pituitary gland, which exert an effect on the ovary. Menstruation is regulated by the hypothalamic-pituitary-ovary (HPO) axis. However, the role of stress in menstruation remains unclear. The objective of this study was to explore the role of stress in endometrial breakdown and shedding, using the pseudopregnant mouse menstrual-like model. Female mice were mated with vasectomized males and labeled day 0.5, upon observation of a vaginal seminal plug. On day 3.5, decidualization was induced in pseudopregnant mice using arachis oil. On day 5.5, pseudopregnant mice with artificial decidualization were placed in restraint tubes for 3 h. The findings indicated that acute restraint stress resulted in the disintegration of the endometrium. While corticosterone concentration in the serum increased significantly due to restraint stress, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and progesterone (P4) levels in the serum decreased significantly. An endometrial histology examination indicated that progesterone implants may rescue P4 decline caused by acute stress and block endometrium breakdown and shedding. In addition, mice were treated with metyrapone, an inhibitor of corticosterone synthesis, 1 h prior to being subjected to restraint stress. Interestingly, metyrapone not only inhibited stress-induced endometrium breakdown and shedding, but also prevented stress-induced reduction of P4, LH and FSH. Furthermore, real-time PCR and western blot showed that mRNA and protein expression of CYP11A1 (cytochrome P450, family 11, subfamily A, polypeptide 1) and steroidogenic acute regulatory protein (StAR), the two rate-limiting enzymes for progesterone synthesis in the ovary, decreased following acute stress. But metyrapone prevented the reduction of StAR expression induced by restraint stress. Overall, this study revealed that acute stress results in an increase in corticosterone, which may inhibit LH and FSH release in the serum and CYP11A1 and StAR expression in the ovary, which finally leads to the breakdown and shedding of the endometrium. These experimental findings, based on the mouse model, may enable further understanding of the effects of stress on menstruation regulation and determine the potential factors affecting stress-associated menstrual disorders.