Efficacy and safety of low dose aspirin plus clopidogrel in the treatment of elderly patients with symptomatic intracranial artery stenosis.

Background: As one of the most common causes of stroke, symptomatic intracranial artery stenosis (sICAS) is a great threat to public health, and its financial burden is substantial, with annual direct high medical costs particularly in China. Currently, the long-term use of conventional dual antiplatelet therapy (DAPT) as the primary modality of treatment for sICAS decreases the risk of stroke recurrence but increases the risk of bleeding. We aimed to evaluate the efficacy and safety of low dose aspirin plus clopidogrel for the treatment of sICAS in the elderly population. Methods: This randomized, controlled study included 181 older patients with transient ischemic attack (TIA) or ischemic stroke (IS) attributed to sICAS, who were recruited between April 2015 and November 2020. The 90 patients assigned to the low dose therapy group included aspirin, 75 mg, plus clopidogrel, 50 mg, daily for 90 and 91 patients assigned to the conventional group included aspirin, 100 mg, plus clopidogrel, 75 mg, daily for 90 days (aspirin or clopidogrel alone daily thereafter) were included in this intention-to-treat analysis. Efficacy and safety analyses were done in this trial. Results: One hundred eighty-one eligible elderly patients with sICAS were enrolled in this trial. The median age was 70 years ranged 60-83 years. Seventy-five participants were with TIA and 106 with IS. The median time of follow-up was 30 months ranged 1-36 months. Ninety patients were assigned randomly to the low dose group and 91 patients to the conventional group. The rate of primary, secondary and composite efficacy were not significantly different between the low dose and conventional group (P > 0.05). The rate of composite safety outcome was 7.8% (7/90) in the low dose group, which was lower than 17.6% (16/91) in the conventional group (χ2 = 3.921, P = 0.048). At the time of last follow-up, 17 (9.4%) of 181 patients developed GI injuries, which occurred in four (4.4%) of 90 patients in the low dose group and in 13 (14.3%) of 91 patients in the conventional group (χ2 = 4.058, P = 0.044). The primary efficacy outcome occurred in six (18.2%) of 33 patients with severe sICAS and in 22 (38.6%) of 57 patients with moderate sICAS (χ2 = 4.064, P = 0.044) in the low dose group. Conclusion: In this study, the safety of low dose aspirin combined with clopidogrel proved to be equally efficient and significantly safer than those of conventional dose within 24 months in elderly patients with sICAS. However, the small size of this study limits the validity of the results. Further larger longitudinal and randomized controlled trials are necessary to evaluate the role of low dose DAPT in the patients with sICAS.

Long-Term Prognostic Factors in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A 15-Year Multicenter Retrospective Study.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multisystem autoimmune disease with small-vessel involvement. In AAV, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are major clinicopathologic variants. In addition, myeloperoxidase (MPO) and proteinase 3 (PR3) are major target antigens. The objective of the study was to explore the predictive factors for long-term survival in AAV patients. Materials and Methods: A multicenter retrospective study was carried out on 407 patients between 2005 and 2020. Clinical parameters were obtained from laboratory tests including the ANCA types, antinuclear antibody (ANA), extractable nuclear antigen (ENA), anti-streptolysin O (ASO), glomerular filtration rate (GFR), and the laboratory examinations for the blood routine, liver function, renal function, and immunity, etc. The data for clinical parameters were collected from electronic medical records (EMRs), and the data for patient survival were acquired through regular follow-up. The association of clinical parameters with overall survival (OS) along with 3-year and 5-year survival rates was analyzed, and the nomogram as a predictive model was established according to the analysis results. Results: In the present study, 336 (82.6%) patients and 46 (11.3%) patients were diagnosed with MPA and GPA, respectively. The mean and median OS for all the patients were 2,285 and 2,290 days, respectively. The 1-year, 3-year, 5-year, and 10-year cumulative survival rates for all the patients were 84.2%, 76.3%, 57.2%, and 32.4%, respectively. Univariate and multivariate survival analyses indicated that the independent prognostic factors included age, pathological categories (MPA, GPA, and other types), serum ANCA types (negative or positive for MPO and/or PR3), ANA, ASO, GFR, lymphocyte, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), and these clinical parameters except for ASO were used to construct a nomogram. The nomogram for 3-year and 5-year survival rates had a C-index of 0.721 (95% CI 0.676-0.766). The calibration curves showed that the predicted values of the nomogram for 3-year and 5-year survival rates were generally consistent with practical observed values, and decision curve analysis (DCA) further demonstrated the practicability and accuracy of the predictive model. Conclusion: Laboratory tests at diagnosis have great significance in the prediction of long-term survival in AAV patients.

Transcriptome analysis and screening of putative sex-determining genes in the invasive pest, Frankliniella occidentalis (Thysanoptera: Thripidae).

The invasive insect pest, Frankliniella occidentalis, is a well-known vector that transmits a variety of ornamental and vegetable viruses. The mechanistic basis of sex determination in F. occidentalis is not well understood, and this hinders our ability to deploy sterile insect technology as an integrated pest management strategy. In this study, six cDNA libraries from female and male adults of F. occidentalis (three biological replicates each) were constructed and transcriptomes were sequenced. A total of 6000 differentially-expressed genes were identified in the two sexes including 2355 up- and 3645 down-regulated genes. A total of 149 sex-related genes were identified based on GO enrichment data and included transformer-2 (tra2), fruitless (fru), male-specific lethal (msl) and sex lethal (sxl); several of these exhibited sex-specific and/or sex-biased expression in F. occidentalis. This study contributes to our understanding of the sex-determined cascade in F. occidentalis and other members of the Thysanoptera.

Identification, expression analysis and functional verification of two genes encoding small heat shock proteins in the western flower thrips, Frankliniella occidentalis (Pergande).

Small heat shock proteins (sHSPs) help prevent the irreversible aggregation of denatured proteins that occurs in response to organismal stress. In this study, we identified two intron-free genes encoding sHSPs from Frankliniella occidentalis; these were designated FoHSP11.6 and FoHSP28.0 and belonged to an atypical and typical sHSP family, respectively. Both FoHSPs were transcribed in all developmental stages of F. occidentalis with the highest expression levels in pupae and adults and greater expression in males than females. Although the FoHSPs had different temperature-induced expression profiles, they were generally induced by both low and high temperatures and reached maximal expression levels after 0.5-1 h of temperature stress. The FoHSPs expression levels in pupae were induced by drought and high humidity, and higher expression levels were correlated with lower survival rates. The thermotolerance of F. occidentalis decreased when theFoHSPs were silenced by RNA interference. Our results show that FoHSP11.6 and FoHSP28.0 are involved in the response to temperature and drought and may also function in growth and development of F. occidentalis.

Tertiary-Amine-Initiated Synthesis of Acyl Fluorides from Carboxylic Acids and CF3 SO2 OCF3.

A convenient method for deoxyfluorination of aromatic and aliphatic carboxylic acids with CF3 SO2 OCF3 in the presence of a suitable base at room temperature has been developed. The reaction allows a straightforward access to a variety of acyl fluorides and proves that CF3 SO2 OCF3 is an effective deoxyfluorination reagent for carboxylic acids. The method features simplicity, expeditiousness, high efficiency, ease of handling, good functional group tolerance, a wide range of substrates, excellent yields of products, compatibility of many amine initiators, use of environmentally friendly reagents, and effortless removal of byproducts. This reaction represents the first utilization of trifluoromethyl trifluoromethanesulfonate as a fluorination reagent.

Fluoroalkylation of Diazo Compounds with Diverse Rfn Reagents.

Progress in the transition-metal-catalyzed or -free fluoroalkylation of diazo compounds with different types of fluoroalkyl (Rfn ) transfer reagents is summarized in this review. Special attention is focused on the straightforward trifluoromethylation, gem-difluoroolefination, trifluoromethoxylation, fluoroalkylthiolation, and trifluoromethylselenolation of diazo substrates. The mechanistic insights and the application of some of the products are also discussed in this article. We believe that this review will inspire both young and experienced chemists to further study the direct fluoroalkylation of diazo compounds as an efficient and convenient way to build complex fluorine-containing molecules.

Concise and Additive-Free Click Reactions between Amines and CF3 SO3 CF3.

Trifluoromethyl trifluoromethanesulfonate has proved to be an excellent reservoir of difluorophosgene and a promising click ligation for amines in the preparation of urea derivatives, heterocycles, and carbamoyl fluorides under metal- and additive-free conditions. The reactions are rapid, efficient, selective, and versatile, and can be performed in benign solvents, giving products in excellent yields with minimal efforts for purification. The characteristics of the reactions meet the requirements of a click reaction. The use of trifluoromethyl trifluoromethanesulfonate as a click reagent is advantageous over other "CO" sources (e.g., TsOCF3 , PhCO2 CF3 , CsOCF3 , AgOCF3 , and triphosgene) because this reagent is readily accessible; easy to scale up; and highly reactive, even under metal- and additive-free conditions. It is anticipated that CF3 SO3 CF3 will be increasingly as important as SO2 F2 as a click agent in future drug design and development.

Astragalus Saponins and Liposome Constitute an Efficacious Adjuvant Formulation for Cancer Vaccines.

Cancer vaccines mostly aim to induce cytotoxic T lymphocytes (CTLs) against tumors. An appropriate adjuvant is of fundamental importance for inducing cellular immune response. Since the antigen in particulate form is substantially more immunogenic than soluble form antigen, it is beneficial to interact with antigen-presenting cells membrane to induce robust CD8+ T cell activation following vaccination. Based on previous research, we designed an adjuvant formulation by combining Astragalus saponins, cholesterol, and liposome to incorporate antigen into a particulate delivery system, so as to enhance cellular immune response. Meanwhile, angiogenesis contributes to tumor growth and metastasis, and basic fibroblast growth factor (bFGF) is involved in tumor angiogenesis. Therefore, using lipo-saponins adjuvant formulation and a human recombinant bFGF antigen protein, we tried to induce bFGF-specific CTL response to inhibit tumor angiogenesis to achieve antitumor activity. After five immunizations, the lipo-saponins/bFGF complex elicited robust antibody response and markedly higher amount of interferon-γ in BALB/c mice, resulting in superior antitumor activities. Decreased microvessel density in CD31 immunohistochemistry and the lysis of vascular endothelial cells by the T lymphocytes from the immunized mice indicated that the immunity inhibited the angiogenesis of tumors and further led to the inhibition of tumors. Our data suggest that the approach to construct adjuvant formulation between liposome and Astragalus saponins appeared highly desirable, and that Astragalus saponins may be utilized as a valuable additive for enhancing the effectiveness of vaccines and stimulating an appropriate immune response that can benefit tumor therapy.

A vaccine targeting basic fibroblast growth factor elicits a protective immune response against murine melanoma.

Tumor growth and metastasis are closely related to angiogenesis. Basic fibroblast growth factor(bFGF) is an angiogenic factor, and up-regulated expression of bFGF plays a crucial role in the development and metastasis of melanoma. Therefore, in this study, we sought to achieve antitumor activity by immunity targeting bFGF which would inhibit tumor angiogenesis and simultaneously induce bFGF specific cytotoxic T lymphocytes to kill melanoma cells. A human bFGF protein was used as exogenous antigen, coupled with a saponin-liposome adjuvant formulation to enhance CTL response. The results showed that the immunity induced strong immune response and produced prominent anti-cancer activities. CD31 immunohistochemistry and alginate-encapsulated tumor cell assay displayed that tumor angiogenesis was effectively inhibited. Further, the higher production of IFN-γ and cytotoxic T lymphocyte killing assay suggested that the anti-cancer activities may mainly depend on cellular immune response, which could cause the inhibition of tumor angiogenesis and specific killing of tumor cells by bFGF-specific cytotoxic T lymphocytes. We concluded that immunotherapy targeting bFGF may be a prominent strategy for melanoma, and that the adjuvant formulation of saponin-liposome is very desirable in enhancing cytotoxic T lymphocytes response.

Sonogashira Reaction Using Arylsulfonium Salts as Cross-Coupling Partners.

Triarylsulfonium, alkyl- and fluoroalkyl(diaryl)sulfonium, and aryl(dialkyl)sulfonium triflates are successfully used as a new family of cross-coupling participants in the Sonogashira reaction as aryldiazonium, diaryliodonium, and tetraphenylphosphonium salts. It was found that terminal alkynes reacted mildly with triarylsulfonium or (2,2,2-trifluoroethyl)diphenylsulfonium triflate at room temperature under Pd- and Cu-cocatalysis to give the corresponding arylalkynes in up to >99% yield. This protocol represents the first use of arylsulfonium salts as cross-coupling partners in the Pd/Cu-catalyzed Sonogashira reaction.

Palladium-catalyzed Mizoroki-Heck-type reactions of [Ph2SRfn][OTf] with alkenes at room temperature.

The first Pd-catalyzed Mizoroki-Heck-type reaction of [Ph2SRfn][OTf] with alkenes is described. The reaction of [Ph2SRfn][OTf] (Rfn = CF3, CH2CF3) with alkenes in the presence of 10 mol% Pd[P(t-Bu)3]2 and TsOH at room temperature provided the corresponding phenylation products in good to high yields. The bases that benefit the traditional Mizoroki-Heck reactions severely inhibited the transformation with [Ph2SRfn][OTf], whereas acids significantly improved the reaction. This protocol supplies a new class of cross-coupling partners for Mizoroki-Heck-type reactions and gains important insights into the reactivity of phenylsulfonium salts either with or without fluorine-containing alkyl groups as the promising phenylation reagents in organic synthesis.

[The bio-effects of high single-dose radiation on xenografts of Lewis lung carcinoma].

OBJECTIVE: To investigate the bio-effects of high single-dose radiation on xenografts of Lewis lung carcinoma. METHODS: Female 8-week-old C57 mice bearing 4-6 mm diameter Lewis lung carcinoma tumors in the hind legs were divided into 3 groups, control group (0 Gy), high single-dose group (12 Gy/one fraction/day) and routine radiation group (22 Gy/11 fraction/15 d). The mean biological effective dose (BED) of both radiation groups was 26.4 Gy. Changes in hypoxia, DNA damage and cell cycle of the tumor cells at 1, 3, 8, 15 and 21 d after first irradiation was assessed by immunofluorescence and flow-cytometry and the tumor growth curve was also made. RESULTS: Compared to the fractionated treatment, the tumor growth was delayed after single dose irradiation. The percent of hypoxic cells after single dose radiation was lower than fractioned irradiation at 3, 8, 15 d after first radiation. The foci of gamma-H2AX showed that the single dose caused heavier DNA damages than fractioned irradiation at 1, 3 d after first radiation. The decline of G0/G1 percentage and increase of G2/M percentage of cells was found in both radiation schedules, but the G2/M percentage after single dose radiation was higher. CONCLUSION: In the C57 mice bearing Lewis lung carcinoma, the high single-dose regimen inhibits the tumor growth more than fractioned irradiation. We hypothesized that conversion of high single-dose to BED using the LQ formalism under estimated the in vivo effect of hypofractionated radiation.