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The JNK signaling pathway plays crucial roles in various physiological processes, including cell proliferation, differentiation, migration, apoptosis, and stress response. Dysregulation of this pathway is closely linked to the onset and progression of numerous major diseases, such as developmental defects and tumors. Identifying and characterizing novel components of the JNK signaling pathway to enhance and refine its network hold significant scientific and clinical importance for the prevention and treatment of associated cancers. This study utilized the model organism Drosophila and employed multidisciplinary approaches encompassing genetics, developmental biology, biochemistry, and molecular biology to investigate the interplay between Tip60 and the JNK signaling pathway, and elucidated its regulatory mechanisms. Our findings suggest that loss of Tip60 acetyltransferase activity results in JNK signaling pathway activation and subsequent induction of JNK-dependent apoptosis. Genetic epistasis analysis reveals that Tip60 acts downstream of JNK, paralleling with the transcription factor FOXO. The biochemical results confirm that Tip60 can bind to FOXO and acetylate it. Introduction of human Tip60 into Drosophila effectively mitigates apoptosis induced by JNK signaling activation, underscoring conserved regulatory role of Tip60 in the JNK signaling pathway from Drosophila to humans. This study further enhances our understanding of the regulatory network of the JNK signaling pathway. By revealing the role and mechanism of Tip60 in JNK-dependent apoptosis, it unveils new insights and potential therapeutic avenues for preventing and treating associated cancers.

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1β release in THP-1 cells, with an IC 50 value of 0.29 μM, approximately 27-fold more potent than that of IAL (IC 50 : 7.86 μM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo . Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.

Hepatocellular carcinoma (HCC) accounts for approximately 90% of all primary liver cancers and is one of the main malignant tumor types globally. It is essential to develop rapid, ultrasensitive, and accurate strategies for the diagnosis and surveillance of HCC. In recent years, aptasensors have attracted particular attention owing to their high sensitivity, excellent selectivity, and low production costs. Optical analysis, as a potential analytical tool, offers the advantages of a wide range of targets, rapid response, and simple instrumentation. In this review, recent progress in several types of optical aptasensors for biomarkers in early diagnosis and prognosis monitoring of HCC is summarized. Furthermore, we evaluate the strengths and limitations of these sensors and discuss the challenges and future perspectives for their use in HCC diagnosis and surveillance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dong, Wang, Yuan, Guo, Yu, Peng, Cai, Xue, Zhou, Sun and Chen.)

Magnolol and honokiol are the two major active ingredients with similar structure and anticancer activity from traditional Chinese medicine Magnolia officinalis, and honokiol is now in a phase I clinical trial (CTR20170822) for advanced non-small cell lung cancer (NSCLC). In search of potent lead compounds with better activity, our previous study has demonstrated that magnolol derivative C2, 3-(4-aminopiperidin-1-yl)methyl magnolol, has better activity than honokiol. Here, based on the core of 3-(4-aminopiperidin-1-yl)methyl magnolol, we synthesized fifty-one magnolol derivatives. Among them, compound 30 exhibited the most potent antiproliferative activities on H460, HCC827, H1975 cell lines with the IC 50 values of 0.63-0.93 μM, which were approximately 10- and 100-fold more potent than those of C2 and magnolol, respectively. Besides, oral administration of 30 and C2 on an H460 xenograft model also demonstrated that 30 has better activity than C2. Mechanism study revealed that 30 induced G0/G1 phase cell cycle arrest, apoptosis and autophagy in cancer cells. Moreover, blocking autophagy by the autophagic inhibitor enhanced the anticancer activity of 30in vitro and in vivo, suggesting autophagy played a cytoprotective role on 30-induced cancer cell death. Taken together, our study implied that compound 30 combined with autophagic inhibitor could be another choice for NSCLC treatment in further investigation., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Eight new flavonoids, including two β-hydroxy/methoxychalcones, velutones A and B ( 1 and 2 ), two 1,3-diarylpropan-1-ols, velutols C and D ( 3 and 4 ), a dihydroxychalcone, velutone E ( 5 ), a chalcone, velutone F ( 6 ), a furanoflavanone, velutone G ( 7 ), and a furanoflavonol, velutone H ( 8 ), and 14 known compounds were isolated from Millettia velutina . Their structures were determined by high-resolution electrospray ionisation mass spectrometry (HR-ESIMS) and spectroscopic data analyses and time-dependent density functional theory electronic circular dichroism (TD-DFT-ECD) calculations. Among the isolated constituents, compound 6 exhibited the most potent inhibitory effect (IC 50 : 1.3 μM) against nigericin-induced IL-1β release in THP-1 cells. The initial mechanism of action study revealed that compound 6 suppressed NLRP3 inflammasome activation via blocking ASC oligomerization without affecting the priming step, which subsequently inhibited caspase-1 activation and IL-1β secretion. Most importantly, compound 6 exerted potent protective effects in the LPS-induced septic shock mice model by improving the survival rate of mice and suppressing serum IL-1β release. These results demonstrated that compound 6 had the potential to be developed as a broad-spectrum NLRP3 inflammasome inhibitor for the treatment of NLRP3-related disease.

Insect-microbial symbioses have vast biochemical diversity, which is beneficial to produce bioactive secondary metabolites. In this study, chemical examination of a Streptomyces sp. associated with a mud dauber wasp led to the isolation of fourteen compounds. Their structures were determined by spectroscopic methods and comparison with literature data. Among the isolates, compounds 1,2,3-benzotriazin-4(1H)-one and 4-(2-aminoethyl)phenyl acetate were first reported from this species. Bioactivities of the isolated compounds were assayed for the first time against hexokinase II. 4-(2-Aminoethyl)phenyl acetate, germicidin B, phenylacetic acid, isogermicidin A and germicidin C displayed significant inhibitory activity against hexokinase II, with the IC 50 values of 5.11, 7.11, 7.15, 8.45 and 8.78 μM, respectively., (© 2020 Wiley-VHCA AG, Zurich, Switzerland.)

Millettia pulchra is a renowned anti-inflammatory herbal medicine in southeast provinces of China. However, the underlying anti-inflammation mechanism remained incompletely understood. Herein, four new isoflavones, pulvones A-D and eleven reported constituents were isolated from the stems of Millettia pulchra with their structures being elucidated by HRMS and NMR analysis. The anti-inflammatory activities of pulvones A and C were further evaluated due to the better inhibitory activity on nitric oxide production in LPS-stimulated RAW264.7 cells and no obvious cytotoxicity to RAW264.7 cells. Western blot showed that pulvones A significantly decreased the levels of iNOS and COX-2 proteins and pulvones C only decreased the level of iNOS protein. ELISA analysis demonstrated that pulvones A inhibited the production of both interleukin-6 (IL-6) and IL-1β while pulvones C showed better suppression effect on IL-1β production in LPS-stimulated RAW264.7 cells. Then, their potential inhibitory effects on NF-κB pathway were tested in LPS-stimulated RAW264.7 cells. Immunofluorescence and western blot assay showed that pulvones A and C reduced the nuclear translocation of NF-κB(p65) and interrupted IκB phosphorylation. The ADP-Glo™ kinase assay showed pulvones A and C could directedly inhibit the IKKβ kinase activity with the inhibitory rate of 40%, which were also verified by docking study. Collectively, these results suggested that pulvones A and C's anti-inflammatory effects were relevant to the interruption of NF-κB activation by inhibiting IKKβ kinase., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In this paper, molecular imprinting and photonic crystal techniques were combined to construct a four-channel sensor array for the simultaneous identification of various sulfonamides. The assay was composed of four units. Three of these units were prepared using sulfaguanidine, sulfamethazine, or sulfathiazole as template molecules. The fourth unit was prepared without a template molecule. The preparation was optimized to obtain maximum identification with a molar ratio of template, monomer, and cross-linker of 1:50:10. The response time was as short as 10 min. For demonstration, six sulfonamides were selected as analytes. The Bragg diffraction patterns of analytes at different concentrations were measured using the sensor array. Data obtained were analyzed using linear discrimination analysis (LDA) and principal component analysis (PCA). LDA can be applied for SAs discrimination. The message ratios of 87.6%, 94.4%, and 95.8% for six SAs at 10 -4  mol L -1 , 10 -6  mol L -1 , and 10 -8  mol L -1 were achieved using LDA. The sensor array identified the mixture containing various SAs with an LDA coefficient of 86.1%, thereby indicating that the sensor array had a strong anti-interference ability. The sensor array was used to identify six SAs in fish samples. The measured data in spiked samples were consistent with the fingerprint collected from standard solutions. The accuracy rate reached 90.9%, indicating that the array can be used to identify SAs from food samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Six new ellagitannins, brevipetins B-G ( 5 and 7 - 11 ), and a new phenolic glucoside, brevipetin A ( 4 ), along with six known compounds were isolated from the traditional Chinese medicinal plant Cleidion brevipetiolatum . Their structures and absolute configurations were determined by spectroscopic analyses, chemical methods, and TD-DFT-ECD calculations. Compounds 5 - 11 exhibited NO inhibitory effects with IC 50 values of 1.9-8.2 μM, and 9 showed the most potent inhibitory effect (IC 50 : 1.9 μM). An in vivo anti-inflammatory assessment of 9 showed that it exerts therapeutic effects in both the carrageenan-induced rat paw edema and collagen-induced arthritis (CIA) models at 50 mg/kg oral administration. The enhanced protein and mRNA expression levels of iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) in LPS-stimulated RAW 264.7 cells were dose-dependently suppressed by 9 . An anti-inflammatory mechanistic study revealed that 9 suppressed NF-κB activity by inhibiting IκBα phosphorylation and blocking translocation of p65 from the cytosol to the nucleus. Therefore, 9 might have the potential to be developed as a lead compound for relieving rheumatoid arthritis.

Two new p-terphenyls, strepantibins A and B (1 and 2), along with the first representative of a naturally occurring bisphenyltropone, strepantibin C (3), were characterized from a Streptomyces sp. associated with the larvae of the mud dauber wasp Sceliphron madraspatanum. Their structures were determined by high-resolution electrospray ionization mass spectrometry, NMR, and X-ray crystallography data interpretation. Strepantibins A-C inhibited hexokinase II (HK2) activity and displayed antiproliferative activity against hepatoma carcinoma cells HepG-2, SMMC-7721 and plc-prf-5. In SMMC-7721 cells treated with strepantibin A, the morphological characteristics of apoptosis were observed.

Four angucycline glycosides were previously characterized from marine-derived Streptomyces sp. OC1610.4. Further investigation of this strain cultured on different fermentation media from that used previously resulted in the isolation of two new angucycline glycosides, vineomycins E and F ( 1 - 2 ), and five known homologues, grincamycin L ( 3 ), vineomycinone B 2 ( 4 ), fridamycin D ( 5 ), moromycin B ( 7 ), and saquayamycin B 1 ( 8 ). Vineomycin F ( 2 ) contains an unusual ring-cleavage deoxy sugar. All the angucycline glycosides isolated from Streptomyces sp. OC1610.4 were evaluated for their cytotoxic activity against breast cancer cells MCF-7, MDA-MB-231, and BT-474. Moromycin B ( 7 ), saquayamycin B 1 ( 8 ), and saquayamycin B ( 9 ) displayed potent anti-proliferation against the tested cell lines, with IC 50 values ranging from 0.16 to 0.67 μM. Saquayamycin B ( 9 ) inhibited the migration and invasion of MDA-MB-231 cells in a dose-dependent manner, as detected by Transwell and wound-healing assays.

Staphylococcus aureus is a major and dangerous human pathogen that causes a range of clinical manifestations of varying severity, and is the most commonly isolated pathogen in the setting of skin and soft tissue infections, pneumonia, suppurative arthritis, endovascular infections, foreign-body associated infections, septicemia, osteomyelitis, and toxic shocksyndrome. Honokiol, a pharmacologically active natural compound derived from the bark of Magnolia officinalis, has antibacterial activity against Staphylococcus aureus which provides a great inspiration for the discovery of potential antibacterial agents. Herein, honokiol derivatives were designed, synthesized and evaluated for their antibacterial activity by determining the minimum inhibitory concentration (MIC) against S. aureus ATCC25923 and Escherichia coli ATCC25922 in vitro. 7c exhibited better antibacterial activity than other derivatives and honokiol. The structure-activity relationships indicated piperidine ring with amino group is helpful to improve antibacterial activity. Further more, 7c showed broad spectrum antibacterial efficiency against various bacterial strains including eleven gram-positive and seven gram-negative species. Time-kill kinetics against S. aureus ATCC25923 in vitro revealed that 7c displayed a concentration-dependent effect and more rapid bactericidal kinetics better than linezolid and vancomycin with the same concentration. Gram staining assays of S. aureus ATCC25923 suggested that 7c could destroy the cell walls of bacteria at 1×MIC and 4×MIC., (Copyright © 2017. Published by Elsevier Ltd.)

A highly selective and sensitive enzyme-linked immunosorbent assay (ELISA) was developed for the detection of malachite green (MG) using a molecularly imprinted polymer (MIP) film as bionic antibody. The MIP film, based on the self-polymerization of dopamine, was fabricated on the surfaces of a 96-well microplate. It showed specific recognition for MG in aqueous solution. A direct competitive ELISA method was established with the sensitivity reaching 10.31μgL -1 and the detection limit being 0.3μgL -1 . The cross-reactivity of two structural analogues to MG was less than 10%. The average recovery tested by MG standard spiking was 88.8% for bass and 90.4% for water, and the relative standard deviations were less than 3.6%. All the above results indicated that the developed method could be used to detect MG in fish and water samples rapidly, specifically and accurately., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A sensitive fluorescence sensor for the detection of malachite green (MG) was fabricated by grafting molecularly imprinted polymers (MIPs) onto the surface of CdTe quantum dots (QDs). The MIP-coated QDs were synthesized via a reverse microemulsion method using (3-aminopropyl)triethoxysilane (APTES) and tetraethyl orthosilicate (TEOS) as functional monomer and cross-linker, respectively. The optimum molar ratio of MG, functional monomer and cross-linker was 1:3:10. The MIP-coated QDs exhibited uniform spheres with diameter around 49nm and excellent fluorescence emission at λ ex 370nm. A linear relationship with two segments between the relative fluorescence intensities and the MG concentrations ranging from 0.08 to 20μmol·L -1 could be obtained with a detection limit of 12μg·kg -1 . The fluorescent probe was successfully applied to the determination of MG in fish samples with the spiked recoveries ranging from 94.3% to 109.5% which were in accordance with those of the measurement by HPLC-UV., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Eleven compounds were successfully separated from Asteris souliei by using a two-step high-performance counter-current chromatography method. The first step involved a reversed phase isocratic counter-current chromatography separation using hexane/ethyl acetate/methanol/water (1:0.8:1:1 v/v/v/v), which produced three fractions, the first two of which were mixtures. The second step used step-gradient reversed-phase counter-current chromatography with hexane/butanol/ethyl acetate/methanol/water (1:0.5:3.5:1:4 v/v/v/v/v) initially followed by hexane/ethyl acetate/methanol/water (1:2:1:2 v/v/v/v) to separate Fraction 1 into seven compounds; and hexane/ethyl acetate/methanol/water (1:1:1:1.2 v/v/v/v) to separate Fraction 2 into three further compounds. The chemical structures of the separated compounds were identified by ESI-MS and NMR spectroscopy ( 1 H and 13 C). Baicalin (5), eriodictyol (7), apigenin-7-glycoside (8), quercetin (9), luteolin (10), and apigenin (11) showed obvious inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells at a concentration of 10 μg/mL., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In the present study, open top chambers (OTCs) were employed to simulate temperature increase at Fenghuoshan site, located on the hinterland of Qinghai-Tibetan Plateau. To explore the potential response mechanism of alpine plants under warmer temperature, the leaf morphological and antioxidative characteristics of two dominant species of alpine meadow (Kobresia pygmaea) and alpine swamp meadow (K. tibetica) were analyzed. The results showed that length and numbers of leaves in K. pygmaea increased by 40.0% and 72.7% by warming, respectively. Plant height and leaf length in K. tibetica increased by 11.9% and 19.3% by warming, respectively. Warming improved plant growth and aboveground biomass accumulation in both species. However, warming did not affect leaf membrane permeability (electrolyte leakage), active oxygen species (hydrogen peroxide and superoxide anion), activities of superoxide dismutase, peroxidase, ascorbate peroxidase and catalase, and malondialdehyde content in both species. Ascorbic acid and free proline contents in K. tibetica increased by 29.8% and 53.8%, respectively, but no change was found in K. pygmaea. In conclusion, K. pygmaea and K. tibetica could adapt under warmer temperature through keeping a steady antioxidative status.

A direct competitive enzyme-linked immunosorbent assay (ELISA) method was used for the detection of malachite green (MG) with a high sensitivity and selectivity using magnetic molecularly imprinted polymers (MMIPs) as a bionic antibody. MMIPs were prepared through emulsion polymerization using Fe 3 O 4 nanoparticles as magnetic nuclei, MG as a template, methacrylic acid (MAA) as a functional monomer, ethylene glycol dimethacrylate (EGDMA) as a crosslinking agent and span-80/tween-80 as mixed emulsifiers. The MMIPs were characterized by scanning electron micrographs (SEM), thermal-gravimetric analyzer (TGA), Fourier transform infrared spectrometer (FT-IR) and vibrating sample magnetometer (VSM), respectively. A high magnetic saturation value of 54.1emug -1 was obtained, resulting in rapid magnetic separation of MMIPs with an external magnet. The IC 50 of the established ELISA method was 20.1μgL -1 and the detection limit (based on IC 85 ) was 0.1μgL -1 . The MMIPs exhibited high selective binding capacity for MG with cross-reactivities less than 3.9% for MG structural analogues. The MG spiking recoveries were 85.0%-106% with the relative standard deviations less than 4.7%. The results showed that the biomimetic ELISA method by using MMIPs as bionic antibody could be used to detect MG rapidly in fish samples with a high sensitivity and accuracy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Five new flavonoids, griffinones A-E (1-5), a new biphenylneolignan, griffilignan A (6) and ten known compounds were isolated from the n-hexane and EtOAc extracts of Millettia griffithii. The structures of the new compounds were determined by 1D and 2D NMR, and by HRMS. The anti-inflammatory activity of the isolated compounds was evaluated on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 cells. Among the isolated compounds, compounds 1, 2 and 14 showed significant anti-inflammatory activity with IC50 values of 20.4, 2.1 and 35.7μM, respectively and no obvious toxicities were observed at 100μM. Western blot and PCR assay further showed that inhibition of nitric oxide production by compound 2 was associated with suppression of iNOS expression. Modeling studies suggested that the amino group, phenyl ring as well as the isopentenyl tails of compound 2 could help bind to iNOs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Magnetic molecularly imprinted polymers (MMIPs) were synthesized through precipitation polymerization using malachite green (MG) as template, methacrylic acid as monomer, ethylene dimethacrylate as crosslinker, and Fe3O4 magnetite as magnetic component. MMIPs were characterized by scanning electron microscopy, Fourier transform infrared spectrometry, and vibrating sample magnetometry. Under the optimum condition, the MMIPs obtained exhibited quick binding kinetics and high affinity to MG in the solution. Scatchard plot analysis revealed that the MMIPs contained only one type of binding site with dissociation constant of 24.0 μg mL(-1). The selectivity experiment confirmed that the MMIPs exhibited higher selective binding capacity for MG than its structurally related compound (e.g., crystal violet). As a sorbent for the extraction of MG in sample preparation, MMIPs together with the absorbed analytes could easily be separated from the sample matrix with an external magnet. After elution with methanol/acetic acid (9:1, v/v), MG in the eluent was determined by high-performance liquid chromatography coupled with UV detector with recoveries of 94.0-115%. Results indicated that the as-prepared MMIPs are promising materials for MG analysis in aquatic products., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Gambogic acid (GA) is in a phase II clinical trial as an antitumor and antiangiogenesis agent. In this study, 36 GA derivatives were synthesized and screened in a zebrafish model to evaluate their antiangiogenic activity and toxicity. Derivatives 4, 32, 35, 36 effectively suppressed the formation of newly grown blood vessels and showed lower toxicities than GA as evaluated by zebrafish heart rates and mortalities. They also exhibited more potent migration and HUVEC tube formation inhibiting activities than GA. Among them, 36 was the most potent one, suggesting that it may serve as a potential new antiangiogenesis candidate with low toxicity. Additionally, 36 showed comparable antiproliferative activity to HUVECs and five tumor cell lines but low cytotoxicity to LO2 cells.

The Co(II) ion in the title complex, [Co(2)(C(4)H(5)O(2))(4)(C(15)H(13)N(5))(2)]·2H(2)O, has a distorted square-planar coordination formed by the bridging bidentate N,N'-di-4-pyridylpyrid-ine-2,6-diamine (dapmp) ligands and two monodentate carboxyl-ate groups from methacrylates. Two dapmp ligands bridge two Co atoms, forming a dinuclear complex arranged around an inversion centre. N-H⋯O and O-H⋯O hydrogen bonds involving the solvent water mol-ecule result in the formation of a three-dimensional network. The aliphatic moiety of one of the methacrylate groups is disordered over two positions with fixed occupancies of 0.67 and 0.33.

Objective: To explore the proportion, clinical and laboratory features, chemotherapy responses and long term survival of different kinds of newly diagnosed multiple myeloma (MM) in China., Methods: The clinical data of 223 cases of newly diagnosed MM patients were gathered in the First Affiliated Hospital of Sun Yat-sen University from Jan, 2000 to Seb, 2007 were retrospectively analyzed., Results: The proportions of each kind of MM including IgG, IgA, light chain, IgD, IgM and biclonal MM were 48.0%, 20.6%, 25.6%, 4.0%, 0.9% and 0.9% respectively. No IgE and nonsecretory myeloma was found. The median age of onset was 58 years, of which that of the IgA type was the oldest one and the light chain type was the youngest (P = 0.004). Bone pain, renal insufficiency, and anemia were the most common symptoms which accounted for 67.7%, 61.0% and 45.3% respectively. The incidences of renal inadequacy, hypercalcemia and pathological fracture in light chain type were higher than those in IgG and IgA types. Besides, no M protein were found in serum protein electrophoresis and no elevation of total globulin. The clinical features of IgD type were similar to that of the light-chain type. The total chemotherapy efficacy rate of 89 patients who were treated with more than 3 cycles in our hospital is 61.8%, which has no difference in all types. Median overall survival of the 89 patients was 33.0 months., Conclusion: IgG is the most common type in MM. Bone pain, anemia, hypercalcemia and renal insufficiency are common symptoms. Immunofixation electrophoresis should be performed routinely to avoid missed diagnosis of light-chain and IgD types of MM.

Background & Objective: Bortezomib, a potent and reversible proteasome inhibitor, induces apoptosis of myeloma cells, resulting in durable responses in patients with multiple myeloma (MM). This study was to explore the medical effects and side effects of bortezomib combined dexamethasone in treating newly diagnosed and relapsed or refractory MM, and evaluate the safety of this regimen in the patients with renal impairment., Methods: Twenty-four MM patients were treated with bortezomib and dexamethasone in a 21-day cycle. The patients received a median of 3 cycles (range, 1-8 cycles) of the treatment. Response to bortezomib was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT); adverse events were graded according to the National Cancer Institute Common Toxicity Criteria., Results: During the follow-up with a median of 4 months, 19 (79.2%) patients responded to the treatment. The complete remission (CR) rate was significantly higher in the patients of light-chain type than in those of non-light-chain type (57.1% vs. 5.9%, P=0.014). The response rates of the patients with and without renal impairment were similar (100% vs. 70.6%, P=0.272), and the renal functions were ameliorated in the patients with renal impairment during chemotherapy. Grade III-IV adverse events, including leucocytopenia (8.3%), thrombocytopenia (33.3%), diarrhea (8.3%) and debility (4.2%), could be relieved by symptomatic treatment or delayed chemotherapy., Conclusions: The combination of bortezomib and dexamethasone shows obvious effects on MM, especially in the patients with light-chain type. The adverse events can be tolerant in most patients, and this regimen is also safe in the patients with renal impairment.

Background & Objective: Busulfan (Bu) is commonly used as a component of conditioning regimens for hematopoietic stem cell transplantation. Erratic gastrointestinal absorption as a result of oral administration of Bu not only affects the efficacy, but also increases the risk of toxicity. This study was to analyze the efficacy and toxicity of intravenous Bu and cyclophosphamide (Cy) conditioning before allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for leukemia., Methods: Fifteen leukemia patients received intravenous Bu/Cy conditioning before allo-PBSCT, while 20 patients received oral Bu/Cy conditioning. The responses and adverse events of the 2 groups were assessed., Results: All 15 patients in intravenous Bu/Cy group had hematopoietic engraftment. The median time of engraftment was 12 (9-15) days for neutrophils and 15 (11-24) days for platelets. Of the 15 patients, 6 (40.0%) developed acute graft-versus-host disease (aGVHD), including 4 cases of grade I-II aGVHD and 2 cases of grade III-IV aGVHD; during conditioning, 7 (46.6%) had vomiting, 1 (6.7%) had oral mucositis, 1 (6.7%) had hemorrhagic cystitis, 2 (13.3%) had hepatic damage, none developed seizure. With a median follow-up of 180 days (range, 35-420 days), 14 (93.3%) patients were alive, 1 died of severe aGVHD accompanied fungal infection of the lung and central nerve system. The occurrence rates of hepatic damage and oral mucositis were significantly lower in intravenous Bu/Cy group than in oral Bu/Cy group (13.3% vs. 60.0%, 6.7% vs. 80.0%, P<0.01). There were no significant differences in hematopoietic reconstruction, aGVHD, stomatitis, gastrointestinal reaction, and hemorrhagic cystitis between the 2 groups (P>0.05)., Conclusion: The intravenous Bu/Cy conditioning before allo-PBSCT for leukemia has clear efficacy with low extramedullary toxicity.

Objective: To retrospectively analyze the curative effects and prognostic factors of HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia patients (CML)., Methods: Of the 35 CML patients, 26 were males and 9 were females, with a median age of 32 (12 - 50) years. 30 patients were in chronic phase of CML, 5 patients were in accelerated phase. Allo-HSCT from HLA identical siblings was performed for 35 patients, of whom 11 received bone marrow transplantation (BMT) and 24 peripheral blood stem cell transplantation (PBSCT). Conditioning regimens was TBI (total-body irradiation) + CY (CTX) protocol in 8 patients and BU/CY protocol in 27 patients. The average follow-up was 48 months (range 7 - 108 months)., Results: 34 (97.1%) patients were successfully engrafted. Among them, 21 patients (60.0%) had three years disease-free (DFS) survival. The overall 5-year survival (OS) was 57.1%. Two patients (5.7%) relapsed. Transplant-related mortality occurred in 12 patients. Hemorrhagic cystitis (HC) occurred in 5 patients and HVOD was observed in 1 patient. Acute graft-versus-host disease (aGVHD) occurred in 18 patients (51.4%), among them 7 patients (20.0%) were of grade III-IV. Chronic GVHD was in 17 patients (48.5%). There was no significant difference in 3-years DFS between BMT group and PBSCT group (54.5% vs. 62.5%, P > 0.05). The 3-year disease-free survival (DFS) was 42.9% in TBI/CY group and 55.6% in BU/CY group (P > 0.05). In univariate prognostic analysis model, the DFS at 3 years is 75% and 47.4% for < or =30 years patients and >30 years patients, respectively, P < 0.05. The 3-year DFS of patients with first chronic phase is higher than patients with advanced diseases (61.3% vs. 40%, P < 0. 05). The 3-year DFS in patients of grade I - II GVHD was higher than that in patients of grade III-IV GVHD (81.8% vs. 14.3%, P < 0.05)., Conclusion: The patients who had transplantation done within 1 year after diagnosis during their first chronic phase of disease and who had low-grade GVHD have better prognosis. Those patients who had III-IV acute GVHD are prone to incorporate severe infection, which was a worse prognostic factor of allo-HSCT for chronic myelogenous leukemia.

Objective: To study the differential expression of four TRAIL receptors on bone marrow mononuclear cells (BMMNC) from multiple myeloma (MM) patients and myeloma cell line KM3 cells, to compare their altered expressions after chemotherapy and to explore the mechanisms by which TRAIL selectively kills tumor cells., Methods: Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry were used to investigate the expression of four TRAIL receptors on BMMNCs in 23 MM patients, KM3 cells and 15 controls, and the changes of their expression pattern after chemotherapy and after incubation of KM3 cells with sub-clinical concentration of doxorubicin., Results: DR4 and DR5 were highly expressed on KM3 cells with no expression of DcR1 and DcR2. Expressions of DR4 and DR5 on BMMNCs from MM patients were higher and expression of DcR1 and DcR2 were lower than that of controls (P < 0.05). The expression of DR5 on MM and KM3 cells was up-regulated after chemotherapy and exposure to doxorubicin (P < 0. 05)., Conclusions: The expressions of four TRAIL receptors on myeloma cells and normal controls were different, which might account for the selective killing effect of TRAIL on MM cells. Up-regulated DR5 on KM3 cells after incubating with doxorubicin and after chemotherapy suggests the cytotoxic agents might enhance the apoptosis of MM cells.

Background & Objective: Chronic myeloid leukemia (CML) in blast phase is refractory with a poor prognosis. This study was to evaluate efficacy of imatinib mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, on CML in blast phase., Methods: Nineteen patients with CML in blast phase (imatinib treatment group) received induction of cytarabine-based standard chemotherapy for 2 cycles, and 400 mg/d of imatinib mesylate for 4 weeks. Patients with no remission received 600 mg/d of imatinib mesylate for another 8 weeks. Treatment of 600 mg/d of imatinib mesylate was maintained if it showed effects after 8 weeks, otherwise it would be stopped. Twenty-two patients with CML in blast phase (historical control group) received inducement of cytarabine-based chemotherapy for 2 cycles, and other regimens of consolidation or continuous induction., Results: Sixteen patients of imatinib treatment group achieved no hematologic remission after induction. After treated with imatinib mesylate, 6 of 16 (38%) achieved hematologic complete remission (CHR), and major cytogenetic response; 2 of 16(13%) achieved hematologic partial remission (PHR); 1 of 16 (6%) returned to chronic phase with minor cytogenetic response. Total hematologic response rate of imatinib treatment group was 57%; 1-year survival rate was 38% (6/16). Eighteen patients of historical control group achieved no hematologic remission after inducement. After treated with other regimens, 2 (11%) achieved CHR, and 1 (6%) achieved PHR. Total hematologic response rate of historical control group was 17%; 1-year survival rate was 6%(1/18), significantly lower than that of imatinib treatment group (P< 0.05)., Conclusions: Imatinib mesylate may have anti-leukemic activity, and prolong survival time of patients with CML in blast phase. But problems of tumor relapse, and drug resistance are still present.

Background & Objective: The mechanism of effect of arsenic trioxide on promyelocytic leukemia is different from that of all-trans retinoic acid. Arsenic trioxide exerts its action by accelerating cell apoptosis, while all-trans retinoic acid by inducing cell differentiation. However, both drugs can inhibit the transcription of tissue factor (TF) mRNA in acute promyelocytic leukemia, and decrease TF level and coagulative activity to normalize coagulopathy. The objective of the study was to observe whether combination of the two drugs could improve efficacy or in contrary accentuate adverse reactions., Methods: Two groups of patients with acute promyelocytic leukemia were included. Twenty-two patients (17 untreated cases and 5 relapsed cases) from January 2000 to October 2001 in group I were treated only with oral retinoic acid [25 mg/(m(2)x d) in two divided doses] for less than 50 days. Nineteen cases (15 untreated cases and 4 relapsed cases) from November 2001 to June 2003) in Group II were treated with combination of arsenic trioxide and all-trans retinoic acid. 0.1% AS2O3 10 ml in 500 ml 5% glucose solution was given intravenously for 4 to 6 hours per day for 28 days. The dosage of retinoic acid in group II was the same as that in group I., Results: Nineteen of 22 cases in retinoic acid-treated group (group I)(16 untreated cases and 3 relapsed cases) achieved complete remission (CR). The CR rate was 86.4%. Seventeen of 19 cases in combination therapy group (group II)(15 untreated cases and 2 relapsed cases) achieved CR. The CR rate was 89.5%. The death rates were 13.6% (3/22, 1 untreated case, 2 relapsed cases) in group I and 10.5% (2/19, 2 relapsed cases) in group II, respectively. The median time to CR was 23 days in group I and 26 days in group II, and the median time to normalization of coagulopathy was 7 days in group I and 4 days in group II. Significant differences were found between the two groups. No significant adverse reaction was observed in both groups., Conclusion: The CR rate and death rate were not different between the two groups. The combination therapy with AS2O3 and all-trans retinoic acid can shorten the time to CR and normalization of coagulopathy.

Background & Objective: The conditioning regimens are the critical factors in the allogeneic hematopoietic stem cell transplantation. This study was conducted to compare the effectiveness and side-effects of two conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HSCT)., Methods: Twenty-one cases received busulfan(BU) 16 mg/kg plus cyclophosphamide(CY) 120 mg/kg,the other 23 cases received total body irradiation(TBI) 7.5-8.5 Gy plus CY 120 mg/kg regimen., Results: The 3-year disease-free survivals (DFS) were 61.5% in BU/CY group and 64.7% in TBI/CY group, respectively (P >0.05). The relapse rates were 23.8% and 26%, respectively, without significant difference (P >0.05). The incidence of liver damage in the BU/CY group was higher (80.9%) than that in the TBI/CY group (54.3%) (P< 0.05), while no case developed hepatic veno-occlusive disease. Stomatitis and gastrointestinal toxicity were significantly lower in the BU/CY group (33.3% and 42.9%) compared with TBI/CY group (78.2% and 78.2%), respectively (P< 0.05). Bladder toxicity (23.8% and 26%) and pulmonary toxicity(14.3% and 13%) were similar in the two groups(P >0.05), while one patient in TBI/CY group developed grade IV pulmonary toxicity, which is lethal. No case was found to have cardiac, renal, or central nervous system grade I toxicity., Conclusion: The two groups have equal effectiveness, BU/CY regimen is relatively easy to administer and well tolerated with low extramedullary toxicity.

Objective: To find sensitive and specific laboratory examination items for early diagnosing and monitoring liver transplantation reject reaction., Methods: Randomly investigate 41 liver transplantation patients, among them there were 16 patients with reject reaction (including 12 with acute rejection, 4 with chronic rejection). Plasma soluble thrombomodulin (STM) and von Willebrand factor (vWF) levels were measured before operation and every other day after operation., Results: Plasma STM level increased significantly after operation, two days before rejection and after acute rejection (5.58 ng/ml +/- 0.42 ng/ml, 5.93 ng/ml +/- 0.45 ng/ml, and 7.88 ng/ml +/- 0.29 ng/ml, respectively), so did vWF level (101.2% +/- 4.68%, 104.3% +/- 5.78%, and 127.7% +/- 5.74%, respectively). STM level was much higher in acute rejection than that in chronic rejection (7.88 ng/ml +/- 0.29 ng/ml vs. 6.35 ng/ml +/- 0.54 ng/ml, t = 2.46, P < 0.05), in no reaction group after impacting therapy than in effective group (8.30 ng/ml +/- 0.19 ng/ml vs. 3.82 ng/ml +/- 0.22 ng/ml, t = 12.98, P < 0.01), and in dead group after treatment than in living group (7.98 ng/ml +/- 0.18 ng/ml vs. 6.51 ng/ml +/- 0.41 ng/ml, t = 3.39, P < 0.01)., Conclusions: Plasma STM and vWF can be taken as laboratory items for monitoring liver transplantation rejection. Plasma STM can act as not only an early prognosticating marker, but also suitable to distinguish acute from chronic reject reaction, and as a marker for monitoring impacting therapy effect and judging prognosis.