Waldenstrom Macroglobulinemia Arising During Maintenance Therapy of Plasma Cell Myeloma.

BACKGROUND: Both plasma cell myeloma (PCM) and Waldenstrom's macroglobulinemia (WM) are mature B-cell neoplasms commonly involving bone marrow and usually related to paraproteinemia. METHODS: Secondary WM in a patient with PCM during maintenance therapy has not been previously reported. We herein report the first case of WM arising during maintenance therapy of PCM. RESULTS: The diagnosis of secondary WM during maintenance therapy of PCM was based on combination of medical history, morphology, flow cytometry, immunofixation electrophoresis, and molecular genetics. CONCLUSIONS: This case highlights the importance of an integrated diagnostic work-up, with an interesting role for morphology and flow immunotyping.

Characterization of a bioactive meroterpenoid isolated from the marine-derived fungus Talaromyces sp.

A new meroterpenoid, taladrimanin A (1), was isolated from a marine-derived fungus Talaromyces sp. HM6-1-1, together with eleven biogenetically related compounds (2-12). A plausible biosynthetic pathway for the meroterpenoids (1-4) was proposed. The planar structure of 1 was assigned by HRESIMS and NMR. Its relative configuration was established by quantum chemical NMR calculation of two possible isomers and analyzed by DP4 + method. Finally, X-ray diffraction unambiguously confirmed the relative configuration and revealed the absolute configuration of compound 1. 2-12 were assigned by comparing their NMR data with those reported in the literature. 1 was the first drimane-type meroterpenoid with a C10 polyketide unit bearing an 8R-configuration. In the bioactive assay, 1 exhibited antitumor activity against gastric cancer cells MGC803 and MKN28; it also inhibited the colony formation and induced apoptosis in MGC803 cells both in a concentration-dependent manner. Additionally, 1 displayed selective antibacterial activity against Staphylococcus aureus 6538P, and low activities towards strains of Vibrio parahaemolyticus and Escherichia coli in this study. KEY POINTS: • Twelve compounds were obtained from Talaromyces sp., including four meroterpenoids, one of which was new. • The new compound taladrimanin A (1) inhibits the growth of gastric cancer cells MGC803 and MKN28 as well as the pathogenic bacteria Staphylococcus aureus 6538P. • The biosynthetic pathway of the meroterpenoids was proposed.

Discovery of UMI-77 as a novel Ku70/80 inhibitor sensitizing cancer cells to DNA damaging agents in vitro and in vivo.

The emergence of chemoresistance poses a significant challenge to the efficacy of DNA-damaging agents in cancer treatment, in part due to the inherent DNA repair capabilities of cancer cells. The Ku70/80 protein complex (Ku) plays a central role in double-strand breaks (DSBs) repair through the classical non-homologous end joining (c-NHEJ) pathway, and has proven to be one of the most promising drug target for cancer treatment when combined with radiotherapy or chemotherapy. In this study, we conducted a high-throughput screening of small-molecule inhibitors targeting the Ku complex by using a fluorescence polarization-based DNA binding assay. From a library of 11,745 small molecules, UMI-77 was identified as a potent Ku inhibitor, with an IC50 value of 2.3 µM. Surface plasmon resonance and molecular docking analyses revealed that UMI-77 directly bound the inner side of Ku ring, thereby disrupting Ku binding with DNA. In addition, UMI-77 also displayed potent inhibition against MUS81-EME1, a key player in homologous recombination (HR), demonstrating its potential for blocking both NHEJ- and HR-mediated DSB repair pathways. Further cell-based studies showed that UMI-77 could impair bleomycin-induced DNA damage repair, and significantly sensitized multiple cancer cell lines to the DNA-damaging agents. Finally, in a mouse xenograft tumor model, UMI-77 significantly enhanced the chemotherapeutic efficacy of etoposide with little adverse physiological effects. Our work offers a new avenue to combat chemoresistance in cancer treatment, and suggests that UMI-77 could be further developed as a promising candidate in cancer treatment.

Ganoderma lucidum polysaccharide inhibits the proliferation of leukemic cells through apoptosis.

OBJECTIVE: To investigate the cytotoxic effect of polysaccharides derived from Ganoderma lucidum on T lymphocyte leukemia cells. METHODS: Water-soluble polysaccharides were extracted from the fruit bodies of G. lucidum, purified, and characterized using HPGPC-MALLS and NMR. The cytotoxicity of G. lucidum polysaccharide fraction 5 (GLP5) to T lymphocyte leukemia cell line Jurkat and human immortalized epidermal cell line HaCat was assessed using MTT assay. Apoptosis was assessed using flow cytometry. Expressions of apoptosis-related genes in the cells after being exposed to GLP5 were detected using Western blot assay. RESULTS: GLP5 was a ß-(1→3) and ß-(1→6) linked glucan. It inhibited the proliferation of Jurkat cells in a concentration-dependent manner and the half-maximal inhibitory concentration (IC50) was 34.5 mg/L but did not suppress the growth of HaCat cells. Apoptotic cells in Jurkat cells were detected to increase with increasing GLP5 concentrations. The expression levels of cleaved caspase-3 were significantly higher after the cells were exposed to 25 and 50 mg/L GLP5 when compared to non-exposed cells (Control). In addition, the expression levels of BAX and Bcl2 were significantly up- and down-regulated after treatment with GLP5 at 25 and 50 mg/L when compared with control (P<0.05), respectively. CONCLUSIONS: GLP5 has antiproliferative activity against Jurkat cells and the activity is likely mediated through the activation of apoptosis pathways.

Environmental investigation of pollutants in coal mine operation and waste dump area monitored in Ordos Region, China.

The increasingly severe emissions of greenhouse and poisonous gases from environmentally unsafe stockpiled coal mine waste dumps have urged people from the academia as well as the industry to focus on environmental impact assessment. In this study, one-year air pollutant monitoring was conducted at the Qipanjing coalfield in Inner Mongolia of China for determining the distribution pattern statue of pollutant exposure and its main driving factors. We used FTIR spectroscopy to measure the inorganic compounds in particulate matter with a diameter of less than 2.5 µm. The spatial and temporal distribution characteristics of leading pollutants, including PM2.5, PM10, SO2, NO2, O3 and CO were analyzed. Firstly, the research showed that the temporal and spatial distribution of pollutants in the coal mine waste area is non-homogeneous. Secondly, some meteorological parameters, such as wind speed, relative humidity, temperature, and rainfall, were found to have significant effects on air pollutant distribution. Stable atmospheric conditions were unfavorable for the diffusion of pollutants and prolong the pollution process. Finally, in the vicinity of coalfields, SO2 and NO2 are present in high concentrations in air. Primary reasons for such high values are coal mining-related activities and active mine fires. This study will help to offer valuable and detailed information for understanding and interpreting the pollution source.

Experimental investigation of temperature distribution and spontaneous combustion tendency of coal gangue stockpiles in storage.

In this study, an experimental model about the coal gangue stockpiles in semi-open storage was developed. According to the model's requirements, the corresponding coal gangues were piled up in the factory building, the heat source and collection points were arranged, and the four operating temperatures were selected from 70 to 350 °C for heating. A series of fire experiments concerning the temperature distributions of the coal gangue piles were conducted systematically. The spontaneous combustion tendency of coal gangue samples under kinds of the four heat sources was analyzed using scanning electron microscope (SEM), thermal gravity analysis, and differential thermal gravity (TG-DTG). Under the action of thermal damage, the surface of micropores in coal gangue becomes rough. Heat accumulation is, in nature, most likely to occur near 0.1~0.4 m away from the heat source of coal pile. Simultaneously, on each of the measured flat layers, the greater the horizontal distance from the heat source is, the lower the heated temperature of gangues is, and the lower the temperature change rate is, indicating that the horizontal heat conduction is also gradually weakened. The experimental model provides an empirical basis for studying the distribution of temperature field in the depth of gangue pile and kinetics reaction mechanism of spontaneous combustion.

Exploring background risk factors for fatigue crashes involving truck drivers on regional roadway networks: a case control study in Jiangxi and Shaanxi, China.

BACKGROUND: Fatigue driving is a leading cause of traffic fatalities and injuries in China, especially among heavy truck drivers. The present study tried to examine which and how factors within the human-vehicle-roadway-environment system contribute to the occurrence of crashes involving fatigued truck drivers. FINDINGS: To reduce such risk on the road, a total of 9168 crashes which occurred in Jiangxi and Shaanxi between 2003 and 2014 were selected to measure the effects of potential factors on fatigue related truck crashes using a case control study. Pearson Chi-square test was used to determine the relationship between crash risk and independent factors, and a stepwise logistic regression model was developed to determine the significant risk factors. According to the data analysis results, driver's gender, age, driving experience, and overspeeding behavior, vehicle's commercial status, overloading conditions and brake performance, road's type, slippery pavement and existence of sharp curve and long steep grade, and time of day, season, weather and visibility conditions, etc. were identified to be significantly associated with fatigue related truck crashes on Jiangxi and Shaanxi highways. Moreover, it is found that (a) in Jiangxi, an employed truck driver has a higher risk of crash involving multi-vehicles or a passenger car at bridge locations, and (b) in Shaanxi, the adult, tunnel location, summer and winter days prohibit statistically significant association with the occurrence of multi-vehicle and single-vehicle run-off-road/rollover crashes. CONCLUSIONS: Young employed male truck drivers with less experience are at high risk, especially while driving across sharp curves, down long steep grades, over bridge or through tunnels, during the midnight period, on rainy, snowy or foggy days in rural areas. All these help recommend potential policy initiatives as well as effective safety promotion strategies at the public health scale for professional truck drivers.