Clinical Characteristics, Treatment, and Prognosis of Osteoarticular Brucellosis: A Retrospective Real-World Study in Shenyang, China, 2014-2019.

This study aimed to assess the clinical characteristics, treatment, and prognosis of osteoarticular brucellosis. We conducted a retrospective study enrolling brucellosis patients from the Sixth People's Hospital of Shenyang between September 2014 and June 2019. A total of 1917 participants were admitted during this period. After applying propensity score matching, we retrospectively analyzed 429 patients with osteoarthritis and 429 patients without osteoarthritis. The primary outcome was treatment completion. The secondary outcome was symptom disappearance and seroconversion. Brucellosis patients with osteoarthritis had longer treatment course (160 [134.3-185.7] vs. 120 [102.3-137.7] d, p = 0.008) than those without osteoarthritis. The most common involved site was lumbar vertebrae (290 [67.6%]) in brucellosis patients with osteoarthritis. Longer symptom duration (90 [83.0-97.0] vs. 42 [40.2-43.8], p < 0.001) along with no significant difference in seroconversion (180 [178.8-181.2] vs. 180 [135.1-224.9], p = 0.212) was observed in osteoarthritis patients with treatment course >90 d. Peripheral joint involvement (adjusted hazard ratio [95% confidence interval] 1.485 [1.103-1.999]; p = 0.009) had a shorter symptom duration compared with shaft joint involvement. No significant differences were observed in treatment therapy between doxycycline plus rifampin (DR) or plus cephalosporins (DRC) in treatment course (p = 0.190), symptom persistence (p = 0.294), and seroconversion (p = 0.086). Lumbar vertebra was the most commonly involved site. Even if all symptoms disappeared, Serum agglutination test potentially remained positive in some patients. Compared with peripheral arthritis, shaft arthritis was the high-risk factor for longer symptom duration. The therapeutic effects were similar between DR and DRC. In summary, our study provided important insights into the clinical characteristics, treatment, and outcomes of osteoarticular brucellosis. Clinical Trial Registration number: NCT04020536.

Natural History of and Dynamic Changes in Clinical Manifestation, Serology, and Treatment of Brucellosis, China.

Serum agglutination test plus exposure history were used to diagnose most cases of human brucellosis in 2 China provinces. After appropriate treatment, 13.3% of acute brucellosis cases progressed to chronic disease; arthritis was an early predictor. Seropositivity can persist after symptoms disappear, which might cause physicians to subjectively extend therapeutic regimens.

Phloroglucinol Benzophenones and Xanthones from the Leaves of Garcinia cowa and Their Nitric Oxide Production and α-Glucosidase Inhibitory Activities.

Five new compounds-two phloroglucinol benzophenones, garciniacowones F (1) and G (2), and three xanthones, garciniacowones H (3), I (4), and J (5)-together with seven known xanthones (6-12) were isolated from the fresh leaves of Garcinia cowa. Their structures were elucidated by detailed analysis of NMR and MS data. Compounds 1 and 2 are phloroglucinol benzophenones containing a polyprenylated bicyclo[3.3.1]nonane ring system, while compounds 3-5 are rare xanthones having farnesyl (3 and 5) and geranylgeranyl (5) units at C-8. Compounds 1, 3, 4, 7, 8, and 10 exhibited inhibitory effects on NO production in LPS-induced RAW264.7 macrophage cells with IC50 values ranging from 5.4 to 18.6 µM. Compounds 4 and 8 had α-glucosidase inhibitory activities with IC50 values of 15.4 and 11.4 µM, respectively, which were more potent than that of the acarbose control.

Amides and Flavonoids from the Fruit and Leaf Extracts of Melodorum siamensis.

Four new chalcones (1, 10, 13, and 14), a new flavanone, (9), a new amide (8), and 19 known compounds were acquired from Melodorum siamensis. The structures were established by NMR and MS data analyses. Compounds 1 (er 1.4:1) and 2 (er 1.1:1) were scalemic and were resolved to yield (-)-1 and (+)-1 and (-)-2 and (+)-2, respectively. The absolute configurations of these compounds were determined from experimental and calculated ECD data. The structures and configurations of (-)-2 and (+)-8 were identified by single-crystal X-ray diffraction analysis. Compound 11 showed nuclear factor-κB inhibitory effects (IC50 = 9 µM) in a pancreatic ß cell line (MIN-6 cells).

Exploring the thermal decomposition and detonation mechanisms of 2,4-dinitroanisole by TG-FTIR-MS and molecular simulations.

2,4-dinitroanisole (DNAN), an insensitive explosive, has replaced trinitrotoluene (TNT) in many melt-cast explosives to improve the safety of ammunition and becomes a promising material to desensitize novel explosives of high sensitivity. Here, we combine thermogravimetric-Fourier transform infrared spectrometry-Mass spectrometry (TG-FTIR-MS), density functional theory (DFT), and ReaxFF molecular dynamics (MD) to investigate its thermal decomposition and detonation mechanisms. As revealed by TG-FTIR-MS, the thermal decomposition of DNAN starts at ca. 453 K when highly active NO2 is produced and quickly converted to NO resulting in the formation of a large amount of Ph(OH)(OH2)OCH3+. DFT calculations show that the activation energy of DNAN is higher than that of TNT due to the lack of α-H. Further steps in both thermal decomposition and detonation reactions of the DNAN are dominated by bimolecular O-transfers. ReaxFF MD indicates that DNAN has a lower heat of explosion than TNT, in accordance with the observation that the activation energies of polynitroaromatic explosives are inversely proportional to their heat of explosion. The inactive -OCH3 group and less nitro groups also render DNAN higher thermal stability than TNT.

B cell receptor signatures associated with strong and poor SARS-CoV-2 vaccine responses.

Breakthrough infection of SARS-CoV-2 is a serious challenge, as increased infections were documented in fully-vaccinated individuals. Recipients with poor antibody response are highly vulnerable to reinfection, whereas those with strong antibody responses achieve sterilizing immunity. Thus far, biomarkers associated with levels of vaccine-elicited antibody response are still lacking. Here, we studied the antibody response of age- and gender-controlled healthy cohort, who received inactivated SARS-CoV-2 vaccines and profiled the B cell receptor repertoires in longitudinally consecutive samples. Upon vaccination, all vaccinated individuals displayed a convergent antibody response with shared common antibody clones and public neutralizing antibodies. Strikingly, poor vaccine-responders are distinguishable from strong vaccine-responders by a biased V-usage before vaccination and IgG to IgM mRNA ratio. These findings reveal molecular signatures associated with the different levels of vaccine-induced antibody response, which could be further developed into biomarkers for the design of vaccination strategies.

Differential enhancement of the anti-cancer effect of doxorubicin by Akt inhibitors on human breast cancer cells with differing genetic backgrounds.

The phosphatidylinositol 3 OH-kinase (PI3K) pathway is a key intracellular signalling cascade in cellular survival. Our previous studies indicated that specific blockade of this enzyme led to sensitisation of human breast carcinoma cells to killing by doxorubicin through induction of both G2 arrest and apoptosis in some, but not all, breast cancer cells. In the present study, we report that inhibition of a down-stream component of this pathway, Akt, is an effective means of enhancing doxorubicin killing in some breast cell types. Doxorubicin (Dox) and six Akt inhibitors were used individually or in combination on MDA-MB-231 (p53 mutant, ER-), T47D (p53 mutant, ER+), and MCF-7 (p53 wt, ER+) human breast cancer cell lines. In MDA-MB-231 breast cancer cells, all six Akt inhibitors, which have differing mechanisms of action to inhibit Akt, synergised with the growth inhibitory effects of doxorubicin. Two Akt inhibitors also enhanced the effect of Dox in T47D cells but the other inhibitors induced additive effects in these cells. None of the inhibitors used elicited enhanced effects in MCF-7 cells. These results support the notion that combination therapies of doxorubicin (and possibly other chemotherapeutics) with inhibitors of elements of the PI3K pathway are a realistic possibility for future breast cancer therapy, which could lead to reduced side-effects, but that this could be dependent on the genetic background of each breast cancer.

Enhanced anti-cancer effect of a phosphatidylinositol-3 kinase inhibitor and doxorubicin on human breast epithelial cell lines with different p53 and oestrogen receptor status.

New efforts are being focused on signalling pathways as targets for cancer therapy. This particular study was designed to investigate whether blockade of the phosphatidylinositol 3OH-kinase (PI3K) pathway (a survival/anti-apoptosis pathway, overexpressed in various tumours) could sensitise human breast cancer cells to the effect of chemotherapeutics. Doxorubicin (Dox) and LY294002 (LY, a PI3K inhibitor) were used individually or in combination on MDA-MB-231 (p53 mutant, ER-), T47D (p53 mutant, ER+), and MCF-7 (p53 wildtype, ER+) human breast cancer cell lines, and on 184A1, a nonmalignant human breast epithelial cell line (p53 wildtype, ER-). Each drug showed time- and dose-dependent growth inhibition of cell proliferation on all 4 cell lines. The combination of Dox+LY resulted in enhanced cell growth inhibition in MDA-MB-231 and T47D cells, and additive inhibition in MCF-7 and 184A1 cells. Cell cycle analysis showed that Dox+LY enhanced the arrest of MDA-MB-231 and T47D cells in G2 with the appearance of a sub-G1 peak indicating apoptosis/necrosis, a notion supported by enhanced depolarisation of mitochondrial membrane potential in these cell types. The combination also caused a greater additive increase in Cyclin B1. Thus, the synergistic effect of the combination on cell proliferation in some, but not all, breast cancer cells may be through enhanced induction of both G2 arrest and apoptosis, in which p53 may play a role. Substantially lower doses of doxorubicin could be used with low doses of inhibitors of the PI3K pathway, without compromising the anti-cancer effect, but also lowering detrimental side-effects of doxorubicin. This study supports the notion that survival signalling pathways offer special targets for chemotherapy in cancer.

Construction of novel conditional transgenic vectors for molecular therapy based on the Tet-On system and flanked with insulators in a single plasmid.

Regulated expression of a gene of interest is crucial for transgenic research, as well as for safe and efficacious gene therapy. The most commonly used conditional expression system requires the generation of two transgenic strains, one carrying an inducible promoter and the other a transactivator. The generation of conditional transgenic models using this method is costly and time consuming. In this study, we report the design and construction of novel simplified gene delivery vectors that integrate both the regulatory and responsive elements in a single vector. The Tet-On system was used and integrated the inducible promoter and transactivator in a single plasmid, between which a copy of an insulator was inserted to minimize interference between the two units. Another copy of an insulator was inserted upstream of the transgene cassette to eliminate transgene silencing and to lower basal expression. The two insulators were in the same orientation. To further decrease basal expression, the most powerful repressor domain containing a 'kruppel-associated box' of the zinc finger protein NK10 was used and fused to TetR in one of the two vectors. The function of this system was confirmed after in?vitro transient transfection. The two conditional plasmids were successfully constructed, and the expression of the gene of interest was regulated tightly in vitro. In conclusion, the vectors described here may be useful for gene therapy applications, as well as for the establishment of conditional animal models.