The beneficial effect of Escalated-R-CHOP-21 for the treatment of diffuse large B-cell lymphoma in elderly male patients: A propensity-matched cohort study.

PURPOSE: Some studies have indicated that using 500 mg/m2 rituximab combined with CHOP-14 may be beneficial for elderly men but not women with diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to investigate the potential benefit of escalated doses of rituximab with CHOP-21 as the first-line treatment in male patients with DLBCL. METHODS: We performed a retrospective cohort study to analyze the survival benefit of rituximab 500 mg/m2 plus the CHOP-21 regimen (Escalated-R-CHOP-21) as the first-line treatment compared with using rituximab 375 mg/m2 plus the CHOP-21 regimen (Standard-R-CHOP-21) in men with DLBCL. We used propensity score matching to maximize the balance of the observed covariables. The primary endpoints of this study were the progression-free survival (PFS) rate and overall survival (OS) rate at 3 years. RESULTS: After a median follow-up of 47 months (IQR 31-65), no significant difference in PFS and OS was found for men treated with Escalated-R-CHOP-21 compared with Standard-R-CHOP-21 [3-year PFS: 69.7% versus 71.9%, p = 0.867; 3-year OS: 83.0% versus 82.4%, p = 0.660]. After 1:1 propensity score matching, we found that the patients using Escalated-R-CHOP-21 had statistically significant survival benefits relative to Standard-R-CHOP-21 among the 96 matched elderly male patients for 3-year PFS [75.5% (95% CI 62.8-88.2) versus 58.2% (95% CI 44.3-72.1); p = 0.019] and 3-year OS [86.6% (95% CI 76.4-96.8) versus 65.8% (95% CI 52.1-79.5); p = 0.017]. However, no differences in survival were observed for younger male patients. Furthermore, the dose effect in PFS of Escalated-R-CHOP-21 was more obvious for elderly male patients with no high-risk extranodal sites (p = 0.005 and interaction p = 0.030). CONCLUSION: Escalated-R-CHOP-21 could be a safe and effective option for treating elderly male patients with DLBCL. This study provides new insight into optimizing the standard treatment regimen, which may have important therapeutic implications in elderly male patients with DLBCL.

VISTA and PD-L1 synergistically predict poor prognosis in patients with extranodal natural killer/T-cell lymphoma.

Although PD-1/PD-L1 blockade therapy confers salutary effects across cancer types, their efficacy in Extranodal Natural killer/T-cell lymphoma (ENKTCL) patients is limited and unpredictable. Here, we comprehensively evaluated the expression profile of a panel of immune-regulatory makers to identify novel prognostic biomarkers and/or therapeutic targets for this malignancy. Using immunohistochemistry and multiplex immunofluorescence, we found that the expression of VISTA (88.1%) was predominantly in CD68+ macrophages and much higher than PD-L1 expression (68.7%) in ENKTCL. B7-H4 and HHLA2 proteins were not detected in ENKTCL. B7-H3 was expressed in minority of ENKTCL patients (13.7%) and mainly colocalized with CD31. A close correlation was detected between VISTA and PD-L1, but they were not co-expressed in the same cells. High expressions of VISTA or PD-L1 were significantly associated with detrimental clinicopathological characteristics, dismal prognosis, and high density of CD8+ TILs, and high VISTA expression was also significantly associated with high density of Foxp3+ TILs. VISTA combined with PD-L1 was an independent prognostic factor for PFS and OS. Moreover, the patients with high VISTA showed a poor response to PD-1 blockades in ENKTCL. In conclusion, these findings provide a rationale for VISTA as an ideal immunotherapeutic target next to PD-L1 for ENKTCL.

Prior anti-PD-1 therapy as a risk factor for life-threatening peri-engraftment respiratory distress syndrome in patients undergoing autologous stem cell transplantation.

Peri-engraftment respiratory distress syndrome (PERDS) is a kind of potentially life-threatening complication of autologous stem cell transplantation (ASCT). PERDS is characterized by fever, dyspnea, and hypoxemia during neutrophil engraftment. In order to identify the high-risk factors for PERDS, we retrospectively analyzed 260 patients with lymphoma undergoing ASCT in recent five years. The conditioning regimen was BuCyE (busulfan, cyclophosphamide, and etoposide). There were 16 patients (6.1%) diagnosed as PERDS. In multivariate analysis, prior anti-programmed death-1 (PD-1) therapy (hazard ratio [HR] = 8.852, 95% confidence interval [CI]: 2.954-26.527, P < 0.001) and history of pulmonary disease (HR = 3.718, 95% CI: 1.197-11.545, P = 0.023) were independent risk factors for PERDS. Patients with prior anti-PD-1 therapy (n = 31) had higher incidence of engraftment syndrome (77.4% vs. 33.4%, P < 0.001), PERDS (25.8% vs. 3.5%, P < 0.001), and transplant-related mortality (9.7% vs. 0.4%, P < 0.001), compared with those without prior anti-PD-1 therapy (n = 229). Subgroup analysis showed that sintilimab seemed to be associated with higher incidence of PERDS (42.9% vs. 11.8%, P = 0.06) compared with non-sintilimab group (pembrolizumab or toripalimab). C-reactive protein might be a feasible early predictor for PERDS. In conclusion, our study suggests that prior anti-PD-1 therapy may be a strong risk factor for life-threatening PERDS in patients with lymphoma undergoing ASCT.

Identifying high-risk patients with natural killer/T-cell lymphoma undergoing autologous stem cell transplantation.

At present, autologous stem cell transplantation (ASCT) is considered as an optional consolidation therapy for natural killer/T-cell lymphoma (NKTCL). However, the high-risk patients undergoing ASCT are not clear enough. In this study, 56 patients with advanced staged or relapsed/refractory (R/R) NKTCL undergoing ASCT were reviewed. All patients achieved clinical complete response (CR) before ASCT. The median follow-up time was 36 months (range, 3-192 months). The three-year overall survival (OS) and three-year progression-free survival (PFS) were 70.2% and 56.5%, respectively. The independent prognostic factors for OS included prior testis involvement and pre-ASCT EBV-DNA. Patients without prior testis involvement and negative pre-ASCT EBV-DNA (group A) had better three-year OS (86.3% vs. 47.6%, p < .001) than the rest patients (group B). In conclusion, our study suggests that testis involvement and elevated EBV-DNA might be strong adverse prognostic factors for NKTCL. Patients without the above risk factors are more likely to benefit from ASCT.

HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma.

BACKGROUND: Although clear cell renal cell carcinoma (ccRCC) is well known as a highly immunogenic tumor, only a small subset of patients could benefit from current immunotherapy, which might be due to the heterogeneity of immune microenvironment in ccRCC. So, it is meaningful to explore novel immunotherapy or combination therapy for improving therapeutic efficacy. HHLA2, a newly discovered B7 family member, is prevalently expressed in numerous tumors, including ccRCC. This study aimed to investigate the prognostic impact of HHLA2/PD-L1 co-expression and its relationship with tumor-infiltrating lymphocytes (TILs). METHODS: The expression levels of HHLA2, PD-L1, CD8, and CD4 in cancer tissues from cases (206 in the training cohort and 197 in the validation cohort) with surgically resectable primary ccRCC were evaluated by immunohistochemistry. RESULTS: The positive rates of HHLA2 were much higher than those of PD-L1 in ccRCC tissues. HHLA2-positive expression was significantly associated with necrosis, microvascular invasion, advanced Fuhrman nuclear, and TNM stage and indicated a shorter progression-free survival (PFS) and overall survival (OS) in both cohorts. Moreover, patients with HHLA2/PD-L1 co-expression suffered the highest risk of disease progression and death by a significant margin. Besides, HHLA2/PD-L1 co-expression was significantly associated with a high density of CD8+ and CD4+ TILs. Notably, a new immune classification, based on HHLA2/PD-L1 co-expression and TILs, successfully stratified PFS and OS, especially in patients with TILs positivity. CONCLUSIONS: The expression of HHLA2 is more frequent than PD-L1 in ccRCC. HHLA2/PD-L1 co-expression had an adverse impact on the prognoses of patients with ccRCC; this finding provides a rationale for combination immunotherapy with anti-HHLA2 and PD-L1 blockage for patients with ccRCC in the future.

Identification and Characterization of a Potential Candidate Mlo Gene Conferring Susceptibility to Powdery Mildew in Rubber Tree.

Mildew resistance locus O (Mlo) gene was first found in barley as a powdery mildew susceptibility gene, and recessive mlo alleles confer durable resistance to barley powdery mildew. To identify candidate Mlo susceptibility genes in rubber tree, HbMlo12 was cloned from rubber tree clone CATAS7-33-97, which is susceptible to powdery mildew. Protein architecture analysis showed that HbMlo12 was a typical Mlo protein with seven transmembrane domains. Protein blast search in the Arabidopsis thaliana proteome database showed that HbMlo12 shared the highest similarity with AtMlo12, with 63% sequence identity. Furthermore, HbMlo12 together with the dicot powdery mildew susceptible Mlo proteins (including AtMlo2, AtMlo6, AtMlo12, tomato SlMlo1, pepper CaMlo2, pea PsMlo1, etc.) were grouped into clade V. Subcellular localization analysis in tobacco epidermal cells revealed that HbMlo12 was localized to the endoplasmic reticulum membrane. HbMlo12 was preferentially expressed in the flower and leaf of rubber tree. Moreover, its expression was significantly upregulated in response to powdery mildew inoculation. Application of exogenous ethephon caused a distinct increase in HbMlo12 expression. Additionally, HbMlo12 transcript was quickly induced by spraying salicylic acid and gibberellic acid and reached the maximum at 0.5 h after treatments. By contrast, HbMlo12 expression was downregulated by methyl jasmonate, abscisic acid, and drought stress treatments. There was no significant change in HbMlo12 expression after indole-3-acetic acid, H2O2, and wounding stimuli. Taken together, these results suggested that HbMlo12 might be a candidate Mlo gene conferring susceptibility to powdery mildew in rubber tree. The results of this study are vital in understanding Mlo gene evolution and developing new rubber tree varieties with powdery mildew resistance using reverse genetics.

Tamsulosin alters levofloxacin pharmacokinetics in prostates derived from rats with acute bacterial prostatitis.

The combination of levofloxacin and α1 adrenergic antagonist treatment is the current preferred choice for both bacterial and non-bacterial prostatitis. The aim of this study is to explore the influence of α1 adrenergic antagonists on the pharmacokinetics of levofloxacin using rat models with acute bacterial prostatitis (ABP) induced by direct injection with Escherichia coli (ATCC25922). A total of 96 model rats were randomly assigned into two groups: the experimental group (treated with both tamsulosin and levofloxacin, n=48) and the control group (treated with levofloxacin and solvents, n=48). Six rats from each group were euthanized to collect blood, liver, kidney and prostate samples at the time points of 0.125, 0.25, 0.5, 1, 2, 4, 8 and 12 h after drug administration. The levofloxacin concentrations were detected by high performance liquid chromatography (HPLC), and the pharmacokinetic parameters were calculated using the 3p97 software program. There were no obvious differences (P>0.05) between the experimental and control groups in the major pharmacokinetic parameters of levofloxacin, including the halftime (t1/2), time to peak (tpeak), clearance rate (CL), maximum concentration (Cmax) and area under the curve (AUC0∼12), in the plasma or in the hepatic and kidney tissues of the model rats. However, in the prostatic tissues, tamsulosin increased the Cmax, prolonged the t1/2 and decreased the CL of levofloxacin (P<0.05). These results indicate that tamsulosin may enhance the effect of levofloxacin in the treatment of bacterial prostatitis without changing the drug concentration in the liver and kidney.

Kaempferol suppresses lipid accumulation in macrophages through the downregulation of cluster of differentiation 36 and the upregulation of scavenger receptor class B type I and ATP-binding cassette transporters A1 and G1.

The accumulation of foam cells in atherosclerotic lesions is a hallmark of early-stage atherosclerosis. Kaempferol has been shown to inhibit oxidized low-density lipoprotein (oxLDL) uptake by macrophages; however, the underlying molecular mechanisms are not yet fully investigated. In this study, we shown that treatment with kaempferol markedly suppresses oxLDL-induced macrophage foam cell formation, which occurs due to a decrease in lipid accumulation and an increase in cholesterol efflux from THP-1-derived macrophages. Additionally, the kaempferol treatment of macrophages led to the downregulation of cluster of differentiation 36 (CD36) protein levels, the upregulation of ATP-binding cassette (ABC) transporter A1 (ABCA1), scavenger receptor class B type I (SR-BI) and ABCG1 protein levels, while no effects on scavenger receptor A (SR-A) expression were observed. Kaempferol had similar effects on the mRNA and protein expression of ABCA1, SR-BI, SR-A, CD36 and ABCG1. The reduced CD36 expression following kaempferol treatment involved the inhibition of c-Jun-activator protein-1 (AP-1) nuclear translocation. The inhibition of AP-1 using the inhibitor, SP600125, confirmed this involvement, as the AP-1 inhibition significantly augmented the kaempferol-induced reduction in CD36 expression. Accordingly, the kaempferol-mediated suppression of lipid accumulation in macrophages was also augmented by SP600125. The increased expression of ABCA1, SR-BI and ABCG1 following kaempferol treatment was accompanied by the enhanced protein expression of heme oxygenase-1 (HO-1). This increase was reversed following the knockdown of the HO-1 gene using small hairpin RNA (shRNA). Moreover, the kaempferol-mediated attenuation of lipid accumulation and the promotion of cholesterol efflux was also inhibited by HO-1 shRNA. In conclusion, the c-Jun-AP­1-dependent downregulation of CD36 and the HO-1-dependent upregulation of ABCG1, SR-BI and ABCA1 may mediate the beneficial effects of kaempferol on foam cell formation.

Heterodichogamy in Kingdonia (Circaeasteraceae, Ranunculales).

BACKGROUND AND AIMS: Preliminary field observations in 2001 and 2002 suggested that Kingdonia uniflora (Circaeasteraceae, Ranunculales) exhibits heterodichogamy, an unusual kind of reproductive heteromorphy, hitherto unreported in Ranunculales and known from only one other genus in basal eudicots. METHODS: During several subsequent years flowers were observed in the field. Flowers were fixed in FAA and studied with microtome sections series and with the scanning electron microscope. KEY RESULTS: The flowers proved to be heterodichogamous, with protandrous and protogynous morphs, which have a 1 : 1 ratio. Both morphs equally set fruit. Each year a single flower is formed at the tip of a rhizome or more rarely two flowers. The flowers are already open when they appear at the soil surface, before they are receptive and before pollen is dispersed. In both floral morphs the styles elongate early and the stigmas are positioned above the anthers before anthesis begins. In protogynous flowers the stigmas become receptive in this position; later the styles become reflexed and then the anthers dehisce. In contrast, in protandrous flowers the stamen filaments elongate during early anthesis such that the dehiscing anthers come to lie above the (still unreceptive) stigmas; after dehiscence of all anthers in a flower the styles begin to elongate and become receptive. CONCLUSIONS: This is the first record of heterodichogamy in a representative of Ranunculales, in an herbaceous eudicot, and in a plant with uniflorous ramets. The occurrence of heterodichogamy in Kingdonia in which clonal reproduction appears to be dominant might be an adaptation to avoid mating between the ramets from a common mother individual (genet).

[Clinical significance of the changes of serum interleukin-18 and tumor necrosis factor-alpha levels in children with infectious mononucleosis].

AIM: To study the dynamic changes of levels of serum interleukin-18 (IL-18) and tumor necrosis factor-alpha (TNF-alpha) in children with infectious mononucleosis (IM). METHODS: 72 patients with IM were analyzed for the expression of TNF-alpha and IL-18 by RIA and ELISA, respectively in acute phase, convalescent phase, (the first month, the third month, the sixth month), and the control group. RESULTS: The levels of serum TNF-alpha and IL-18 in patients with IM were significantly higher than that in control (P < 0.05). The serum levels of TNF-alpha and IL-18 decreased with time and in patients at stage were significantly higher than that in control (P < 0.05). The levels of serum cytokine were correlated with the state of illness. CONCLUSION: The serum cytokine TNF-alpha and IL-18 may be regarded as index to reflect the state of immunity and prognosis of patients with IM.

[Detection of the expression of transgene in rice plant based on hyperspectral remote sensing technique].

The present study aims to identify the expression of transgene in given rice plant samples in certain conditions. To avoid external noise caused by temperature change and water-loss, field spectrum was collected with ASD field spectrometer in natural state. The study calculated the mean spectrum of samples as main data set analyzed which were controlled by inner clustering coefficient to ensure data quality. By mean spectrum, the noise from random distinctions in few individual cultivators, which could not be expressed in the class stably, could be weakened even with filtering. With the help of parameters, such as red edge and green peak, this study gave qualitative spectral differences between transgenic samples and their parents. The results show that the transgenes in rice plant were expressed and influenced the samples. Moreover, it was found that the parameters of area are more suitable for describing the differences/changes of the samples, while PRI and SR-PRI are more sensitive to indicate them. Most of the above results could be found on the continuum-removal spectrum curve of samples. These conclusive results demonstrate that hyperspectral remote sensing technique has good prospects and application potential in transgene expression detection and monitoring, especially in plant breeding process.

[Correlation of the expression of survivin and caspase-3 proteins in juvenile laryngeal papilloma].

AIM: To investigate correlation between the expression of survivin and caspase-3 proteins in juvenile laryngeal papilloma. METHODS: The expression of survivin and caspase-3 proteins were detected with immunohistochemical method in 43 cases of juvenile laryngeal papilloma, 25 vocal nodules and 25 normal laryngeal mucosa. RESULTS: The positive rates of survivin protein in juvenile laryngeal papilloma were 57.14% and higher than that in vocal nodules (P<0.01) and the normal laryngeal mucosa (P<0.01). And the Caspase-3 protein positive rate was 26.19% in juvenile laryngeal papilloma and lower than that in vocal nodules and the normal laryngeal mucosa (P<0.01). There was a significant negative correlation between the expression of survivin and caspase-3 in juvenile laryngeal papilloma. CONCLUSION: The abnormal expression of survivin and caspase-3 may play important role in the pathogenesis of juvenile laryngeal papilloma.

[Bioequivalence of enteric coated tablet of Zhengqing Fengtongning].

OBJECTIVE: To explore the pharmacokinetics and bioequivalence of two kinds of enteric coated tablet of Zhengqing Fengtongning. METHOD: A single dose of 45 mg kg(-1) test or reference preparation was administrated by randomized crossover way in 12 rabbits. The plasma concentrations of drug were determined by HPLC. The pharmacokinetics parameters and relative bioequivalence were calculated with 3p97 program. RESULT: The concentration curves based on drug-time of both test and control preparations were presented by one-compartment model, tmax were (0.81 +/- 0.34), (0.60 +/- 0.30) h respectively, Cmax were (11.16 +/- 0.58), (11.90 +/- 1.44) microg mL(1) respectively, AUC(0-->t) were (61.58 +/- 6.70), (60.56 +/- 6.67) microg h mL(-1) respectively, relative bioavailability was (102.77% +/- 15.63)%. Suggesting no significant diffirence between the main pharmacokinetic parameters of two prepations. CONCLUSION: The two preparations are bioequivalent.