Two new quinazoline alkaloids produced by Aspergillus versicolor and their antimicrobial activities.

Two new quinazoline alkaloids versicomides G-H (1 and 2), together with seven known compounds, were isolated from Aspergillus versicolor HYQZ-215 obtained from the sediment of Qarhan Salt Lake. Their structures were elucidated by NMR, HRESIMS, and quantum chemical ECD calculations data. The antimicrobial activities of these compounds were evaluated against seven agricultural pathogenic fungi and eight clinically drug-resistant bacteria.

Effect of early mobilization on the development of pneumonia in patients with traumatic brain injury in the neurosurgical intensive care unit: A historical controls study.

BACKGROUND: Pneumonia has a high incidence in traumatic brain injury (TBI) patients and lacks effective treatments. Early mobilization (EM) may be a potentially effective treatment. AIM: To explore the impact of EM on TBI-related pneumonia in the neurosurgical intensive care unit (NICU). STUDY DESIGN: This study was a historical control study. 100 TBI patients who received EM intervention were prospectively included as the experimental group (EM cohort), and 250 TBI patients were retrospectively included as the control group. The propensity score matching (PSM) method was employed to balance baseline and minimize potential bias. The relationship between EM and TBI-related pneumonia was investigated by univariate and multivariate logistic regression, then further determined by subgroup analysis. The influence of other variables was excluded by interaction analyses. Finally, the effect of EM on the prognosis of TBI patients was analysed by comparing the Glasgow Coma Scale (GCS) and the hospital stay. RESULTS: After screening, 86 patients were included in the EM cohort and 199 patients were included in the control cohort. There were obvious differences between the two cohorts at baseline, and these differences were eliminated after PSM, when the incidence of pneumonia was significantly lower in the EM cohort than in the control cohort (35.0% vs. 61.9%, p < .001). Multivariate logistic regression showed that EM was an independent risk factor for TBI-related pneumonia and was significantly associated with a decreased incidence of pneumonia. This correlation was present in most subgroups and was not affected by other variables (p for interaction >.05). Patients in the EM cohort had shorter length of ICU stay (6 vs. 7 days, p = .017) and higher GCS at discharge (12 vs. 11, p = .010). CONCLUSION: EM is a safe and effective treatment for TBI patients in NICU, which can reduce the incidence of pneumonia, help to improve prognosis and shorten the length of ICU stay. RELEVANCE TO CLINICAL PRACTICE: Although the utilization rate of EM is low in TBI patients for various reasons, EM is still an effective method to prevent complications. Our study confirms that a scientific and detailed EM strategy can effectively reduce the incidence of pneumonia while ensuring the safety of TBI patients, which is worthy of further research and clinical application.

Nucleophilic Allylation of Acylsilanes in Water: An Effective Alternative to Functionalized Tertiary α-Silylalcohols.

A nucleophilic allylation of acylsilanes in water was developed, generating versatile functionalized tertiary α-silyl alcohols in high yields. With the assistance of hydrogen bonding, a reaction model of less reactive acylsilane was achieved. Unlike the conventional strategy, transition metals and an additional Lewis acid catalyst were not required, and rate acceleration was observed in water.

Friedel-Crafts Reaction of Acylsilanes: Highly Chemoselective Synthesis of 1-Hydroxy-bis(indolyl)methanes and 1-Silyl-bis(indolyl)methanes Derivatives.

A novel double Friedel-Crafts reaction of acylsilanes in water is described. This strategy enables synthesis of bis(indolyl)methane derivatives with 1-hydroxy or 1-silyl substituents in moderate to high yield. Compared to the 1-silyl-bis(indolyl)methane derivatives from indole substrate, 1-hydroxy-bis(indolyl)methane derivatives were synthesized from the 5-hydroxyindole, and the hydrogen bonds in the 5-hydroxyindole play a crucial role in regulating the reaction selectivity.

Lenvatinib with or without immune checkpoint inhibitors for patients with unresectable hepatocellular carcinoma in real-world clinical practice.

BACKGROUND: Lenvatinib is regarded as the first-line therapy for patients with unresectable hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of lenvatinib with or without immune checkpoint inhibitors (ICIs) in patients with unresectable HCC. METHODS: In this multicentric retrospective study, patients with unresectable HCC who treated with lenvatinib with or without ICIs would be enrolled. Overall survival, progression-free survival, objective response rate, and disease control rate were calculated to assess the antitumor response. RESULTS: Between January 2019 and August 2020, 65 patients received lenvatinib plus ICIs while other 45 patients received lenvatinib. The baseline characteristics were comparable between the two groups. Lenvatinib plus ICIs provided significantly higher overall survival (hazard ratio = 0.47, 95% CI 0.26-0.85; p = 0.013) and progression-free survival (hazard ratio = 0.35, 95% CI 0.20-0.63; p < 0.001) than lenvatinib monotherapy. Moreover, patients with lenvatinib plus ICIs had significantly higher objective response rate (41.5% vs 20.0%, p = 0.023) and disease control rate (72.3% vs 46.7%, p = 0.009) per RECIST v1.1 than those with lenvatinib. No treatment-related deaths were observed. Grade 3 or greater adverse events occurring in 10% or more of patients in either treatment group were hypertension [13 (20.0%) of 65 patients treated with lenvatinib plus ICIs vs 8 (17.8%) of 45 patients treated with lenvatinib], and palmar-plantar erythrodysesthesia [seven (10.8%) vs two (4.4%)]. CONCLUSIONS: In this real-world study, lenvatinib combined with ICIs showed significantly promising efficacy and manageable safety than lenvatinib alone in patients with unresectable HCC.

Machine Learning-Driven 3D Plasmonic Cavity-in-Cavity Surface-Enhanced Raman Scattering Platform with Triple Synergistic Enhancement Toward Label-Free Detection of Antibiotics in Milk.

The surface-enhanced Raman scattering (SERS) technique with ultrahigh sensitivity has gained attention to meet the increasing demands for food safety analysis. The integration of machine learning and SERS facilitates the practical applicability of sensing devices. In this study, a machine learning-driven 3D plasmonic cavity-in-cavity (CIC) SERS platform is proposed for sensitive and quantitative detection of antibiotics. The platform is prepared by transferring truncated concave nanocubes (NCs) to an obconical-shaped template surface. Owing to the triple synergistic enhancement effect, the highly ordered 3D CIC arrays improve the simulated electromagnetic field intensity and experimental SERS activity, demonstrating a 33.1-fold enhancement compared to a typical system consisting of Au NCs deposited on a flat substrate. The integration of machine learning and Raman spectroscopy eliminates subjective judgments on the concentration of detectors using a single feature peak and achieves accurate identification. The machine learning-driven CIC SERS platform is capable of detecting ampicillin traces in milk with a detection limit of 0.1 ppm, facilitating quantitative analysis of different concentrations of ampicillin. Therefore, the proposed platform has potential applications in food safety monitoring, health care, and environmental sampling.

New chromone analog and pyrrole alkaloid produced by Penicillium sclerotiorum and their antibacterial activity.

A new chromone analog (1) and a new pyrrole alkaloid (2), together with four known compounds, were isolated from the endophytic fungus Penicillium sclerotiorum MPT-250 obtained from the stems of Taxus wallichiana var. chinensis (Pilger) Florin. The structural elucidation of these metabolites was performed by high-resolution mass spectrometry and NMR spectroscopy. Compounds 1 and 5 exhibited significant antibacterial activity against carbapenems-resistant Pseudomonas aeruginosa and multidrug-resistant Enterococcus faecium with an minimum inhibitory concentration (MIC) value of 3.13 µg/ml respectively.

[Ubiquitin-conjugating enzyme UBE2Q2 participates in HUWE1-mediated protection on renal tubulointerstitial fibrosis].

The ubiquitin-proteasome system plays an important role in protein degradation. The process of ubiquitination requires ubiquitin activating enzyme E1, ubiquitin-conjugating enzyme E2, and ubiquitin ligase E3 to complete the coordination. Our previous studies have shown that HUWE1 (HECT, UBA and WWE domain containing 1), as an E3 ubiquitin ligase, can degrade epidermal growth factor receptor (EGFR) to inhibit renal tubulointerstitial fibrosis. However, E2 ubiquitin-conjugating enzymes binding to HUWE1 are still unclear. The aim of the present study was to identify E2 ubiquitin-conjugating enzymes of HUWE1. Real-time PCR was used to identify E2 ubiquitin-conjugating enzyme that may interact with HUWE1. The expression of E2 ubiquitin-conjugating enzyme was detected in kidney of unilateral ureteral obstruction (UUO) mice and HK-2 cells treated with transforming growth factor-ß (TGF-ß). The results showed that the expressions of E2 ubiquitin-conjugating enzyme UBE2Q2 were significantly down-regulated at both RNA and protein levels in UUO kidneys. The expression of UBE2Q2 was also down-regulated in HK-2 cells stimulated with TGF-ß, which was consistent with the change in the expression of HUWE1. These findings indicated that UBE2Q2 expression was synergistic with HUWE1 in the injured kidney. Co-immunoprecipitation (Co-IP) experiments showed that HUWE1 interacted with UBE2Q2 in HK-2 cells. The co-localization of UBE2Q2 and HUWE1 was confirmed by cell immunofluorescence staining. After knocking down UBE2Q2 by siRNA, ubiquitin binding to HUWE1 and EGFR was decreased. In sum, our results demonstrated that UBE2Q2, ubiquitin-conjugating enzyme, works with HUWE1 to mediate ubiquitination and degradation of target protein in kidney.

[Efficacy Evaluation of Three Endoscopic Therapies of Isolated Gastric Varices with Modified Tissue Adhesive].

Objective: To evaluate the efficacy of three endoscopic therapies of isolated gastric varices (IGV) with modified tissue adhesive. Methods: A retrospective analysis was conducted with the clinical data of 73 IGV patients who were treated between January 2008 and December 2019 at Beijing Ditan Hospital. Patient clinical data on age, sex, etiology, biochemistry findings, Child-Pugh classification, the type of spontaneous shunt, preoperative bleeding history, and the presence or absence of liver cancer were collected. The three therapies evaluated were endoscopic intravenous injection of tissue glue combined with lauromacrogol, endoscopic clip-assisted intravenous injection of tissue glue combined with lauromacrogol, and endoscopic clip and LOOP-assisted intravenous injection of tissue glue combined with lauromacrogol. Their respective clinical treatment outcomes, including ectopic embolism rate, survival rate, rebleeding rate, amount of lauromacrogol and tissue glue used, the number of endoscopic clips used, and the number of times of the procedure the patient underwent, were evaluated. Results: In the patient baseline data, Child-Pugh grade, preoperative thrombus formation, and the presence or absence of liver cancer, showed significant difference between the three therapies ( P<0.05). There was no significant difference in the rates of ectopic embolism among the three methods ( P>0.05), but no ectopic embolism occurred after endoscopic clip-assisted intravenous injection of tissue glue combined with lauromacrogol, or after endoscopic clip and LOOP-assisted intravenous injection of tissue glue combined with lauromacrogol. There was no significant difference in the survival rate, the rebleeding rate, amount of lauromacrogol and tissue glue used for the three therapies, but there was significant difference in the number of endoscopic clips used and the number of times the procedure was conducted within one year ( P<0.05). Conclusion: The two endoscopic therapies of intravenous injection of modified tissue glue, one assisted by clip and the other assisted by clip and LOOP, can help reduce the number of procedures IGV patients undergo within one year.

Enhanced anti-melanoma efficacy through a combination of the armed oncolytic adenovirus ZD55-IL-24 and immune checkpoint blockade in B16-bearing immunocompetent mouse model.

Although the recent treatment in melanoma through the use of anti-PD-1 immunotherapy is successful, the efficacy of this approach remains to be improved. Here, we explore the feasibility of combination strategy with the armed oncolytic adenovirus ZD55-IL-24 and PD-1 blockade. We find that combination therapy with localized ZD55-IL-24 and systemic PD-1 blockade leads to synergistic inhibition of both local and distant established tumors in B16-bearing immunocompetent mouse model. Our further mechanism investigation reveals that synergistic therapeutic effect is associated with marked promotion of tumor immune infiltration and recognition in both local and distant tumors as well as spleens. PD-1 blockade has no obvious effect on promotion of tumor immune infiltration and recognition. Localized therapy with ZD55-IL-24, however, can help PD-1 blockade to overcome the limitation of relatively low tumor immune infiltration and recognition. This study provides a rationale for investigation of such combination therapy in the clinic.

MiR-200a with CDC7 as a direct target declines cell viability and promotes cell apoptosis in Wilm's tumor via Wnt/ß-catenin signaling pathway.

MiR-200a acts as a key role in tumor malignant progression. This work purposed to assess the function of miR-200a in Wilm's tumor. Based on bioinformatics analysis, the expression, prognostic value and related pathways of miR-200a and CDC7 (a potential downstream molecule of miR-200a) in Wilm's tumor were analyzed. qRT-PCR was conducted to confirm the miR-200a level in Wilm's tumor cells. The luciferase reporter assay was carried out to verify the binding of miR-200a to 3'-UTR of CDC7. Then, the impacts of miR-200a and CDC7 on cell viability and apoptosis were measured using CCK-8 and flow cytometry assays. Also, western blot was applied to measure the expression of CDC7 as well as Wnt/ß-catenin signaling pathway-related proteins and apoptosis proteins. Herein, we revealed that miR-200a was lowly expressed in Wilm's tumor tissues and cells and the low miR-200a expression is closely bound up with death and poor outcomes. Moreover, miR-200a directly targeted and inhibited CDC7 in Wilm's tumor cells. Biological function experiments illustrated that overexpression of miR-200a reduced the viability and elevated the apoptosis of Wilm's tumor cells, while overexpression of CDC7 reversed the inhibitory impact of miR-200a on cell viability and the promoting impact of miR-200a on cell apoptosis. Besides, we revealed that miR-200a/CDC7 axis can decrease the expression of ß-Catenin, Cyclin D1 and C-Myc as well as the phosphorylation of GSK-3ß, thus inhibiting the Wnt/ß-catenin signaling pathway. Furthermore, blocking the Wnt/ß-catenin signaling pathway caused an increase on cell apoptosis, while overexpression of CDC7 can reverse these impacts. Collectively, miR-200a/CDC7 axis involved in regulating the malignant phenotype of Wilm's tumor through Wnt/ß-catenin signaling pathway, which provides a theoretical basis for targeted molecular therapy of Wilm's tumor.

A pediatric case of primary amoebic meningoencephalitis due to Naegleria fowleri diagnosed by next-generation sequencing of cerebrospinal fluid and blood samples.

BACKGROUND: Primary amoebic meningoencephalitis (PAM) is a rare, acute and fatal disease of the central nervous system caused by infection with Naegleria fowleri (Heggie, in Travel Med Infect Dis 8:201-6, 2010). Presently, the majority of reported cases in the literature have been diagnosed through pathogen detection pathogens in the cerebrospinal fluid (CSF). This report highlights the first case of pediatric PAM diagnosed with amoeba infiltration within CSF and bloodstream of an 8-year-old male child, validated through meta-genomic next-generation sequencing (mNGS). CASE PRESENTATION: An 8-year-old male child was admitted to hospital following 24 h of fever, headache and vomiting and rapidly entered into a coma. CSF examination was consistent with typical bacterial meningitis. However, since targeted treatment for this condition proved to be futile, the patient rapidly progressed to brain death. Finally, the patient was referred to our hospital where he was confirmed with brain death. CSF and blood samples were consequently analyzed through mNGS. N. fowleri was detected in both samples, although the sequence copy number in the blood was lower than for CSF. The pathogen diagnosis was further verified by PCR and Sanger sequencing. CONCLUSIONS: This is the first reported case of pediatric PAM found in mainland China. The results indicate that N. fowleri may spread outside the central nervous system through a damaged blood-brain barrier.

Ferulic Acid Ameliorates Isoproterenol-Induced Heart Failure by Decreasing Oxidative Stress and Inhibiting Cardiocyte Apoptosis via Activating Nrf2 Signaling Pathway in Rats.

Ferulic acid (FA) has potential therapeutic effects in multiple diseases including cardiovascular diseases. However, the effect and molecular basis of FA in heart failure (HF) has not been thoroughly elucidated. Herein, we investigated the roles and mechanisms of FA in HF in isoproterenol (ISO)-induced HF rat model. Results found that FA ameliorated cardiac dysfunction, alleviated oxidative stress, reduced cell/myocardium injury-related enzyme plasma level, inhibited cardiocyte apoptosis in ISO-induced HF rat models. Moreover, FA reduced the co-localization of Keap1 and nuclear factor-E2-related factor 2 (Nrf2) in heart tissues of ISO-induced HF rats, and FA alleviated the inhibitory effects of ISO on expressions of p-Nrf2, heme oxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (NQO1). Additionally, Nrf2 signaling pathway inhibitor ML385 showed adverse effects. FA weakened the effects of ML385 in ISO-induced HF rat models. Collectively, FA ameliorated HF by decreasing oxidative stress and inhibiting cardiocyte apoptosis via activating Nrf2 pathway in ISO-induced HF rats. Our data elucidated the underling molecular mechanism and provided a novel insight into the cardioprotective function of FA, thus suggested the therapeutic potential of FA in HF treatment.

Two glyoxylate reductase isoforms are functionally redundant but required under high photorespiration conditions in rice.

BACKGROUND: The glyoxylate reductase (GR) multigene family has been described in various plant species, their isoforms show different biochemical features in plants. However, few studies have addressed the biological roles of GR isozymes, especially for rice. RESULTS: Here, we report a detailed analysis of the enzymatic properties and physiological roles of OsGR1 and OsGR2 in rice. The results showed that both enzymes prefer NADPH to NADH as cofactor, and the NADPH-dependent glyoxylate reducing activity represents the major GR activity in various tissues and at different growth stages; and OsGR1 proteins were more abundant than OsGR2, which is also a major contributor to total GR activities. By generating and characterizing various OsGR-genetically modified rice lines, including overexpression, single and double-knockout lines, we found that no phenotypic differences occur among the various transgenic lines under normal growth conditions, while a dwarfish growth phenotype was noticed under photorespiration-promoted conditions. CONCLUSION: Our results suggest that OsGR1 and OsGR2, with distinct enzymatic characteristics, function redundantly in detoxifying glyoxylate in rice plants under normal growth conditions, whereas both are simultaneously required under high photorespiration conditions.

Alterations in intra- and internetwork functional connectivity associated with levetiracetam treatment in temporal lobe epilepsy.

OBJECTIVE: Levetiracetam (LEV) is an antiepileptic drug with a novel pharmacological mechanism. Advances in functional magnetic resonance imaging (fMRI) enable researchers to explore the cognitive effects of antiepileptic drugs on the living brain. This study aimed to explore how the functional connectivity patterns of the cognitive networks changed in association with LEV treatment. METHODS: Patients with temporal lobe epilepsy (TLE), including both users and nonusers of LEV, were included in this study along with healthy controls. Core cognitive networks were extracted using an independent component analysis approach. Functional connectivity patterns within and between networks were investigated. The relationships between functional connectivity patterns and clinical characteristics were also examined. RESULTS: The patterns of intranetwork connectivity in the default mode network (DMN), left executive control network (lECN), and dorsal attention network (DAN) differed among the three groups. The internetwork interactions did not show intergroup differences once corrected for multiple comparisons. No correlation between functional connectivity and clinical characteristics was found in patients with TLE. CONCLUSIONS: Changes in intranetwork connectivity are a key effect of LEV administration. SIGNIFICANCE: Alterations in intranetwork connectivity patterns may underlie the cognitive effects of LEV administration; this finding improves our understanding of the neural mechanisms of LEV therapy.

ILK promotes survival and self-renewal of hypoxic MSCs via the activation of lncTCF7-Wnt pathway induced by IL-6/STAT3 signaling.

Mesenchymal stem cells (MSCs) have been applied in treating various diseases including myocardial infarction (MI) and achieved a bit of success; however, the decreased survival rate of MSCs after transplantation greatly limited the efficacy for cell therapy. How to improve the MSC survival rate in stem cell transplantation has undoubtedly become urgent and genetic engineering may be an ideal and feasible way. In this study, we explored the effects on MSCs survival and self-renewal by overexpression of integrin-linked kinase (ILK) in MSCs under hypoxic stimulation and aimed to reveal the molecular mechanisms from the point of paracrine function of MSCs. We first found that overexpression of ILK induced the expression and secretion of IL-6 increased significantly in MSCs under hypoxic stimulation, and the survival and self-renewal of MSCs exposed to hypoxia were enhanced after ILK overexpression. Then the activation of JAK2/STAT3 signaling was detected because of the increased IL-6, and an lncRNA, named lncTCF7, was upregulated remarkably, promoting the activation of Wnt pathway that was required for keeping cell viability and stemness of MSCs. Moreover, we further verified that inhibition of STAT3 signaling by WP1066 and silencing lncTCF7 expression eliminated the protective effects of ILK overexpression on cell survival and self-renewal of MSCs under hypoxic sitmulation. In conclusion, our results uncovered a novel function of ILK to promote MSC survival and self-renewal, suggesting more application potentials of MSC cell therapy on MI.

Prognosis of clear cell renal cell carcinoma (ccRCC) based on a six-lncRNA-based risk score: an investigation based on RNA-sequencing data.

BACKGROUND: The scientific understanding of long non-coding RNAs (lncRNAs) has improved in recent decades. Nevertheless, there has been little research into the role that lncRNAs play in clear cell renal cell carcinoma (ccRCC). More lncRNAs are assumed to influence the progression of ccRCC via their own molecular mechanisms. METHODS: This study investigated the prognostic significance of differentially expressed lncRNAs by mining high-throughput lncRNA-sequencing data from The Cancer Genome Atlas (TCGA) containing 13,198 lncRNAs from 539 patients. Differentially expressed lncRNAs were assessed using the R packages edgeR and DESeq. The prognostic significance of lncRNAs was measured using univariate Cox proportional hazards regression. ccRCC patients were then categorized into high- and low-score cohorts based on the cumulative distribution curve inflection point the of risk score, which was generated by the multivariate Cox regression model. Samples from the TCGA dataset were divided into training and validation subsets to verify the prognostic risk model. Bioinformatics methods, gene set enrichment analysis, and protein-protein interaction networks, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses were subsequently used. RESULTS: It was found that the risk score based on 6 novel lncRNAs (CTA-384D8.35, CTD-2263F21.1, LINC01510, RP11-352G9.1, RP11-395B7.2, RP11-426C22.4) exhibited superior prognostic value for ccRCC. Moreover, we categorized the cases into two groups (high-risk and low-risk), and also examined related pathways and genetic differences between them. Kaplan-Meier curves indicated that the median survival time of patients in the high-risk group was 73.5 months, much shorter than that of the low-risk group (112.6 months; P < 0.05). Furthermore, the risk score predicted the 5-year survival of all 539 ccRCC patients (AUC at 5 years, 0.683; concordance index [C-index], 0.853; 95% CI 0.817-0.889). The training set and validation set also showed similar performance (AUC at 5 years, 0.649 and 0.681, respectively; C-index, 0.822 and 0.891; 95% CI 0.774-0.870 and 0.844-0.938). CONCLUSIONS: The results of this study can be applied to analyzing various prognostic factors, leading to new possibilities for clinical diagnosis and prognosis of ccRCC.

A quantitative spectral component analysis method based on maximum likelihood.

In spectroscopy, the compositional analysis of the spectrum is important, such as extracting information about the species of spectral objects contributing to spectral data from an emission spectrum of photon energy. A quantitative spectral component analysis method based on Maximum Likelihood Estimation using Expectation Maximization (MLEM) is developed, which could quantitatively decompose out the components of the measured spectrum of low counts and surpass conventional techniques which belong to classification or regression. Abundant experimental and simulated spectra data on gamma-ray spectrum of radionuclides are presented to demonstrate and evaluate this method, while the ingredient radionuclides in the mixed spectrum are identified accurately with high precision. It will be a powerful and alternative method recommended for the circumstances needing fast and quantitative spectral analysis, including radionuclide identification (gamma-ray spectra), biomass or mineral composition (near-infrared spectra), laser-induced breakdown spectra and other spectroscopy scenarios.

Randomized, double-blind, placebo-controlled phase I dose escalation study of Dan Qi Tong Mai tablet in healthy volunteers.

BACKGROUND: This study aims to assess the tolerability and safety of DQTM tablet, which contains a complex mixture of Salvia miltiorrhiza salvianolic acids and Panax notoginseng saponins. METHODS: A double-blind, randomized, placebo-controlled phase I dose escalation study was conducted in 84 healthy volunteers. In a single ascending dose study, active ingredients were administered in various doses (90, 270, 540, 1080, 1800, 2880, 4320 or 5760 mg) to 60 subjects in cohorts 1-8. In a multiple ascending dose study, active ingredients were administered at doses of 360, 720 or 2160 mg twice daily to 24 subjects in cohorts 9-11 for 14 consecutive days. Safety was evaluated based on clinical symptoms, vital signs, physical examinations, electrocardiography, laboratory tests and adverse events. RESULTS: No serious adverse events or clinically significant changes in vital signs or electrocardiography were observed. One subject experienced mildly elevated levels of alanine aminotransferase and aspartate transaminase but recovered spontaneously. Five subjects experienced a small increase in the number of daily stools. CONCLUSIONS: DQTM tablet was well tolerated at single doses of up to 5760 mg and twice-daily doses of up to 2160 mg for 14 consecutive days. The most frequent adverse event was an increase in the number of daily stools.