[Clinical study on the effect of etoposide-containing induction regimen for adult-onset Still's disease associated hemophagocytic syndrome].

Objective: To investigate the efficacy of an etoposide-containing regimen in the treatment of adult-onset Still's disease related hemophagocytic syndrome(AOSD-HLH). Methods: This study adopted the method of retrospective analysis to collect clinical data of 43 AOSD-HLH patients, including the clinical characteristics, laboratory indexes, treatment regimen and prognosis. There were 7 males and 36 females, aged 24-40 years, with a median age of 30. All of them were diagnosed and treated in Beijing Friendship Hospital of Capital Medical University from December 2014 to December 2019. According to whether or not etoposide (VP-16) was included in the initial therapy, patients were divided into group 1 (VP-16 was not administrated in the initial treatment, n=31) and group 2 (the initial treatment included etoposide, n=12). Patients in group 1 who did not respond to the initial treatment were retreated with VP-16-containing regimen, and the effect of initial treatment was compared between the 2 groups. Similarly, according to whether the VP-16-containing regimen was applied or not, patients achieving remission of HLH were divided into group a (not applied, n=6) and group b (applied, n=33), and the laboratory indicators of the two groups were compared. Results: The overall response rate (ORR, 6/31 vs 11/12) and complete response rate (CRR, 1/31 vs 5/12) of patients in group 1 were significantly lower than those in group 2 (both P<0.05). Patients in group 1 who did not respond to the initial treatment were retreated with a VP-16-containing regimen, and we found that the ORR reached 22/24. Among patients in remission, the natural killer cell activity [16.3(14.2, 17.5)% vs 13.1(12.2, 13.8)%] and granulocyte counts [5.6(3.4, 9.3) ×109/L vs 3.9(2.3, 4.7) ×109/L] of patients was significantly higher in group B than that in group A(both P<0.05). There was no statistically significant difference in haemoglobin [103.0 (97.0, 109.5) g/L vs 91.5 (70.0, 118.0) g/L] and platelet counts [(212.2±74.2)×109/L vs (226.0±114.9)×109/L] between the two groups(both P>0.05). Conclusion: The remission status of HLH has an impact on the prognosis of patients. The use of VP-16 in initial treatment can significantly increase the ORR and CRR of AOSD-HLH patients. The application of VP-16 does not cause bone marrow suppression.

Changes in intestinal florae and serum inflammation in rheumatoid arthritis rats and the effects of probiotics.

OBJECTIVE: The aim of this study was to explore the changes in intestinal florae and serum inflammation in rats with rheumatoid arthritis (RA), and to investigate the effects of probiotics. MATERIALS AND METHODS: A total of 30 Sprague Dawley (SD) rats were randomly divided into three groups, namely, control group, model group, and probiotic group. The rats in the model group were prepared into models of collagen II-induced arthritis. Meanwhile, the rats in probiotic group were treated with probiotics for 6 weeks via intragastric administration in addition to the treatment in the model group. Next, the feces of rats in the control group, model group, and probiotic group were sampled to detect the composition of intestinal florae. In addition, peripheral blood was collected from rats to determine the changes in the content of inflammatory factors, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1ß through enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the control group, the levels of serum inflammatory factors TNF-α, IL-6 and IL-1ß were significantly upregulated in the model group (p<0.05). This suggested successful modeling. However, they decreased notably in probiotic group when compared with the model group (p<0.05), indicating that probiotics could inhibit inflammatory response in rats. The levels of microbes Bacteroidetes, Streptococcus and Clostridiales were significantly higher in the control group (p<0.05). The levels of Ruminococcaceae, Asoccbarobacler, Coriobacteriaceae, and fecal anaerobic coryneform bacteria were remarkably higher in the model group (p<0.05). Meanwhile, the levels of Porphyromonadaceae, Barnsiella, Actinobacteria, Alloscardovia, Bifidobacteria and Parabacteroides were remarkably higher in probiotic group (p<0.05). The intestinal level of Bacteroides was the highest in rats of control group, which decreased significantly in the model group (p=0.000). However, the intestinal level of Bacteroides in probiotic group was overtly higher than that in the model group (p=0.000), whereas was lower than the control group. The intestinal level of Bifidobacteria in the model group was significantly lower than that in the control group (p=0.024). However, it was evidently higher in the probiotic group than that in both model group and control group (p=0.000). The intestinal level of Asoccbarobacler was remarkably higher in the model group than that in control group (p=0.005). However, it was lower in probiotic group than that in model group (p=0.003), showing the highest in model group. There was an evidently negative correlation between Firmicuteria and Clostridium (r=-0.82, p=0.000), and a positive association between Firmicuteria and Bacteroides (r=0.77, p=0.000). Bacteroides was negatively correlated with Clostridium (r=-0.89, p=0.002) and Enterococcus (r=-0.63, p=0.021). In addition, Enterococcus had a highly positive correlation with Clostridium (r=0.6, p=0.001). CONCLUSIONS: Evident changes in intestinal florae and serum inflammation are detected in rats with RA, and such changes can be partially reversed by probiotics.

[Clinical study of haploidentical hematopoietic stem cell transplantation on 15 cases of adult-onset primary hemophagocytic lymphohistiocytosis].

Objective: This study was designed to evaluate the efficacy of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for adult-onset primary hemophagocytic lymphohistiocytosis (HLH) . Method: A retrospective study was carried out to analyze the clinical data of 15 adult patients with primary HLH who received haplo-HSCT from January 2013 to October 2019 in Beijing Friendship Hospital, Capital Medical University, Beijing, China. Results: Among the 15 patients included in the study, ten were males and five were females, with a median age of 21 years old (18-52) . Eight of the patients had familial hemophagocytic lymphohistiocytosis type 2 (FHL-2) , four had FHL-3, one had Griscelli syndrome type 2 (GS-2) , one had X-linked lymphoproliferative disease type 1 (XLP-1) , and the other had XLP-2. The median time from HLH diagnosis to transplantation was 7 months (2-46 months) . Seven patients were treated with Bu/Cy condition regimen prior to transplantation. Meanwhile, the other eight cases were treated with TBI/Cy. The median concentration of mononuclear cell (MNC) infusion was 12.6 (9.2-20.3) ×10(8)/kg and CD34(+) cells was 4.91 (2.51-8.37) ×10(6)/kg. The median time of leukocyte engraftment was on day 13 following transplantation (10-23 days) , and the platelet engraftment was on day 12 (9-36) . Graft failure (GF) finally occurred in two patients (one primary GF and one secondary GF) . The cumulative incidence of acute graft-versus-host-disease (GVHD) grades 2 to 4 was 71.4% (10/14) and chronic GVHD was 30.8% (4/13) , respectively. The five-year overall survival (OS) for all 15 cases of primary HLH was 65.5% (95% CI, 34.9%-73.3%) and the transplant-related mortality (TRM) was 26.7% (4/15) . The five-year OS was 87.5% (95% CI, 38.7%-66.3%) in eight patients who received haplo-HSCT subsequent to initial therapy and 42.9% (95% CI, 8.5%-65.2%) in patients seven patients who needed salvage therapy prior to haplo-HSCT (χ(2)=2.387, P=0.122) . The five-year OS was 85.7% (95% CI, 50.4%-89.8%) in eight patients who achieved complete response before haplo-HSCT and 42.9% (95% CI, 6.4%-53.0%) in seven patients with partial response (χ(2)=3.185, P=0.074) . Conclusion: The results indicated that haplo-HSCT is a promising method for the treatment of primary HLH in adults.

Linc00702 inhibits cell growth and metastasis through regulating PTEN in colorectal cancer.

OBJECTIVE: To elucidate the expression and influence of Linc00702 on the development and progression of colorectal cancer (CRC). PATIENTS AND METHODS: The expression of Linc00702 was evaluated using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) in 91 paired CRC tissue samples and adjacent normal tissue samples, as well as in CRC cell lines. Cell proliferation in Caco2 and SW620 cells was detected using colony formation assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay. Wound-healing assay and transwell analysis were utilized to assess the abilities of cell migration and invasion. Western blot analysis was employed to further explore the underlying mechanism of Linc00702 in CRC. RESULTS: Linc00702 was lowly expressed in CRC tissues and cells. Over-expression of Linc00702 reduced cell proliferation, migration, and invasion of Caco2 cells, while knockdown of Linc00702 promoted cell growth and metastasis of SW620 cells comparing to control group, relatively. PTEN was verified as the target for Linc00702 in CRC, and Linc00702 promoted PTEN expression to inhibit the PI3K/AKT pathway. CONCLUSIONS: Linc00702 was downregulated in CRC and inhibited cell proliferation, migration, and invasion by repressing the PI3K/AKT pathway via promoting PTEN expression. This might provide a new target for the biological treatment for CRC.

[Clinical analysis of patients with hemophagocytic lymphohistiocytosis complicated with gastrointestinal bleeding].

Objective: To explore the clinical features of patients with hemophagocytic lymphohistiocytosis (HLH) complicated with gastrointestinal bleeding. Methods: The clinical data of 52 patients with HLH diagnosed from January 2015 to February 2017 were analyzed retrospectively. Results: ①Of the 52 patients[including 36 cases of EBV related (69.2%) , 5 cases of lymphoma related (9.6%) , 3 cases of primary HLH (5.8%) , 3 cases of rheumatism related (5.8%) , 2 cases of tuberculosis related (3.8%) , 3 cases of unknown causes (3.8%) ], 32 cases were male (61.5%) and 20 cases female (38.5%) with a median age of 26 (6-64) years old. ②The overall survival rates at 1, 3, 6 and 12 months were 74.7%, 53.8%, 32.9% and 23.3% respectively. ③Multivariate analysis (logistic regression) showed thrombocytopenia (P=0.036) and other sites of hemorrhage (P=0.030) were risk factors of poor prognosis, and allogeneic hematopoietic stem cell transplantation (allo-HSCT, P=0.026) was the influence of good prognostic factor. Conclusion: HLH combined with gastrointestinal bleeding was an entity of disease with poor prognosis. Thrombocytopenia and other sites of bleeding had a significant negative impact on patients, allo-HSCT produced a significant positive impact on patients.

The SUMO-specific protease SENP5 controls DNA damage response and promotes tumorigenesis in hepatocellular carcinoma.

OBJECTIVE: SUMOylation plays critical roles in a variety of physiological and pathological processes including tumorigenesis. SUMOylation is a reversible process which is mediated by the SENP (Sentrin/SUMO-specific protease) family to remove SUMO from conjugated substrates. SENP5 has been reported to play critical roles in the control of several cancers including breast cancer, osteosarcoma and oral squamous cell carcinoma. In this study, we uncovered a role of SENP5 in promoting tumorigenesis process in hepatocellular carcinoma (HCC) via regulating DNA damage response. MATERIALS AND METHODS: The mRNA and protein levels of SENP5 in 10 pairs of HCC samples were determined by Realtime PCR and Western blot, respectively. SiRNAs were used to silence the expression of SENP5 in HepG2 cells. Male BALB/c nude mice were used to determine the roles of SENP5 on tumorigenesis. In vivo SUMOylation assay was used to detect the SUMOylation of ATRIP. Immunoprecipitation (IP) was used to detect the interaction between SENP5 and ATRIP. RESULTS: We found that SENP5 was over-expressed in HCC samples and required for HCC cells proliferation both in vitro and in vivo. SENP5-depleted HepG2 cells exhibited hypersensitivity to IR and etoposide treatment with defective checkpoint activation including decreased activation of ATR and phosphorylation of ATR targets. At the molecular level, we found that SENP5 interacted with ATRIP and promoted ATRIP deSUMOylation. CONCLUSIONS: Overall, our data suggest that SENP5 is required for HCC cell growth and might be a promising drug target for HCC.

[The role of theophylline in the improvement of scop-induced learning and memory impairment].

Adenosine and ACh contents in hippocampus, striatum region around the nucleus of basal meynert (NBM) and the frontal and temporal parts of rat cortex were measured by a high performance liquid chromotography-electronic detector (HPLC-ECD). Adenosine content in 18~20 month-old rats was significantly higher than that of 3~6 month-old rats, while ACh content in 18~20 month-old rats was lower than that of 3~6 month-old ones. Learning and memory impairment models were established by induction of SD rats with scopolamine (0.5 mg/kg, ip), which were injected with an adenosine receptor antagonist theophylline (1.0 mg/5 microliter, icv), and the step-down test was performed. The error frequency in the step-down test decreased significantly (P<<0.05), and the retention time was longer than that of control. Furthermore, ACh content increased in all the three different brain regions. The above results suggest that adenosine may play an important role in senile learning and memory impairment, and theophylline may improve scopolamine-induced learning and memory impairment by increasing ACh content. In consequence, theophylline could be a promising drug for ameliorating senile learning and memory impairment.

Age-dependent change in the inhibitory effect of an adenosine agonist on hippocampal acetylcholine release in rats.

To investigate the possibility that age-dependent deficits in acetylcholine (ACh) release are precipitated by the alteration of endogenous purinergic activities, the effects of (-)N6-phenylisopropyladenosine (PIA), an adenosine agonist, in modulating K+ (25 mM)-induced [3H]ACh release from the hippocampal slices of young (3-6 months old) and old rats (26-30 months old) were examined. In young rats, PIA (0.1-10 microM) caused a dose-related inhibition of [3H]ACh release from the hippocampal slices and a significant reduction in [3H]ACh release was observed in the presence of 1 microM PIA. In old rats, a similar pattern of PIA suppression of K(+)-induced [3H]ACh release was observed; however, a 10-fold higher concentration of PIA (10 microM) was required to elicit a significant inhibition. This age-dependent reduction in responsiveness to PIA may be due to an enhanced endogenous adenosine activity in aged rats leading to downregulation of the adenosine receptors. This notion is supported by the finding that both the adenosine concentration and activity of 5'-nucleotidase, an enzyme partially governing adenosine synthesis, were increased in the hippocampus of old rats as compared to their younger counterparts.

Decrease in cold tolerance of aged rats caused by the enhanced endogenous adenosine activity.

During severe cold exposure, old rats (24-28 months) were less capable of maintaining their body temperature compared to young rats (3-6 months) due to lower rate of heat production. Single injection of adenosine deaminase (AD) (converts adenosine to inosine) significantly increased thermogenesis in both young and old rats. However, doubling the dose of AD was required for optimal thermogenic response in old rats. In contrast, the similar enhancements in both thermogenesis and cold tolerance were observed in both young and old rats receiving the same optimal doses of specific adenosine receptor antagonists. These results lead to the suggestion that the lower capability of aged rats to withstand cold exposure could be due to an increase in adenosine stimulation because of the decreased endogenous AD activity rather than an increase in adenosine receptor sensitivity. This notion is further supported by the finding that the AD activity in the neck muscle, a key site for shivering thermogenesis, was significantly lower in old rats as compared to their younger counterparts before and after cold exposure.

Analysis of volatile N-nitrosamines in beer and food in China.

Capillary gas chromatography-thermal energy analysis was used for the study of volatile N-nitrosamines in comestibles. The finding of a comparatively high content of N-nitrosodimethylamine in some Chinese beers confirms the results of other authors. We describe studies of Chinese foods and environmental samples carried out in this laboratory in collaboration with epidemiological groups. The concentrations of N-nitrosamines could be correlated with mortality from digestive cancer.

High-performance liquid chromatographic studies of environmental carcinogens in China.

A review of high-performance liquid chromatographic (HPLC) studies of environmental carcinogens in China is presented, including the HPLC analysis of the ubiquitous polynuclear aromatic hydrocarbons (PAHs) and of nitro-substituted PAHs and aflatoxins. Some results of applying these methods to air particulates, emissions, smoke from coal combustion and water and to the inhibition of benzo[a]pyrene metabolism are reported.

Potent mutagenic impurities in a commercial sample of 3-nitro-9-fluorenone.

A commercial sample of 3-nitro-9-fluorenone was a potent mutagen in the Ames Salmonella assay, producing 1000 TA98 net revertants per plate at 0.76 microgram/plate without the presence of liver homogenates (-S9). After purification by high-pressure liquid chromatography (HPLC), 3-nitro-9-fluorenone was found to be at least 6 times less active than the parent sample. The commercial sample was fractionated by HPLC and the mutagenic impurity peaks collected and subjected to high-resolution mass spectrometry (HRMS). The mass spectra of 2 potent mutagenic fractions showed the principal molecular species to be a dinitrofluorenone and an acetamidomononitrofluorenone. Samples of synthetic 2,7-dinitro-9-fluorenone and 2-acetamido-3-nitro-9-fluorenone had mutagenic activities, HPLC retention times, and mass spectra characteristics similar to the mutagenic impurity fractions collected from the commercial sample.