In vitro and in vivo cancer cell apoptosis triggered by competitive binding of Cinchona alkaloids to the RING domain of TRAF6

TRAF6 is highly expressed in many tumors and plays an important role in the immune system. The aim of this study is to confirm anti-tumor activities of all naturally occurring Cinchona alkaloids that have been screened using computational docking program, and to validate the accuracy and specificity of the RING domain of TRAF6 as a potential anti-tumor target, and to explore their effect on the immune system. Results reported herein would demonstrate that Cinchona alkaloids could induce apoptosis in HeLa cells, inhibit the ubiquitination and phosphorylation of both AKT and TAK1, and up-regulate the ratio of Bax/Bcl-2. In addition, these compounds could induce apoptosis in vivo, and increase the secretion of TNF-α, IFN-γ, and IgG, while not significantly impacting the ratio of CD4⁺T/CD8⁺T. These investigations suggest that the RING domain of TRAF6 could serve as a de novo biological target for therapeutic treatment in cancers.     

Calorimetric Study of Nonspecific Interaction Between Lead Ions and Bovine Serum Albumin

The nonspecific interaction between lead ions and bovine serum albumin (BSA) was studied by the calorimetric technique. According to thermodynamic parameters calculated from titration curves, it can be seen that the increase of intermolecular bond energies and decrease of disorder in the system were accompanied by a binding process. This kind of binding is the reaction “driven by enthalpy.” Furthermore, the denatured BSA has more binding sites and more changes in enthalpy and entropy than the native BSA because the unfolded chain of denatured BSA could adapt itself to the binding reaction with lead ions more easily.     

Structural Insights into ceNAP1 Chaperoning Activity toward ceH2A-H2B

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MAGE genes: Prognostic indicators in AL amyloidosis patients

A high frequency of MAGE‐CT (cancer testis) antigens are expressed in Multiple Myeloma (MM) patients; however, in other plasma cell dyscrasias, their potential function remains unclear. We measured the expression of MAGE‐CT genes (MAGE‐C1/CT7, MAGE‐A3, MAGE‐C2/CT10) in 105 newly diagnosed amyloid light‐chain (AL) amyloidosis patients between June 2013 and January 2018 at Peking University People's Hospital using real‐time quantitative polymerase chain reaction. In the newly diagnosed AL patients, the positive expression rates of patients with MAGE‐C1/CT7, MAGE‐C2/CT10 and MAGE‐A3 were 83.8% (88/105), 56.71% (38/67) and 22.0% (13/59) respectively. There was no significant correlation between organ propensity and MAGE‐CT gene expression. Changes in the MAGE‐C1/CT7 levels were consistent with a therapeutic effect. The expression levels of MAGE‐C1/CT7, MAGE‐C2/CT10 and MAGE‐A3 provide potentially effective clinical indicators for auxiliary diagnoses and monitoring treatment efficacy in AL amyloidosis patients.     

Production of nanocellulose by enzymatic hydrolysis: Trends and challenges

There is a great interest in increasing the levels of production of nanocellulose, either by adjusting production systems or by improving the raw material. Despite all the advantages and applications, nanocellulose still has a high cost compared to common fibers and to reverse this scenario the development of new, cheaper, and more efficient means of production is required. The market trend is to have an increase in the mass production of nanocellulose; there is a great expectation of world trade. In this sense, research in this sector is on the rise, because once the cost is not an obstacle to production, this material will have more and more market. Production of the cellulose fibers is determinant for the production of nanocellulose by a hydrolyzing agent with a reasonable yield. This work presents several aspects of this new material, mainly addressing the enzymatic pathway, presenting the hydrolysis conditions such as pH, biomass concentration, enzymatic loading, temperature, and time. Also, the commonly used characterization methods are presented, as well as aspects of the nanocellulose production market.     

Degenerate Connective Polypeptide 1 (CP1) Domain from Human Mitochondrial Leucyl-tRNA Synthetase

The connective polypeptide 1 (CP1) editing domain of leucyl-tRNA synthetase (LeuRS) from various species either harbors a conserved active site to exclude tRNA mis-charging with noncognate amino acids or is evolutionarily truncated or lost because there is no requirement for high translational fidelity. However, human mitochondrial LeuRS (hmtLeuRS) contains a full-length but degenerate CP1 domain that has mutations in some residues important for post-transfer editing. The significance of such an inactive CP1 domain and a translational accuracy mechanism with different noncognate amino acids are not completely understood. Here, we identified the essential role of the evolutionarily divergent CP1 domain in facilitating hmtLeuRS''s catalytic efficiency and endowing enzyme with resistance to AN2690, a broad-spectrum drug acting on LeuRSs. In addition, the canonical core of hmtLeuRS is not stringent for noncognate norvaline (Nva) and valine (Val). hmtLeuRS has a very weak tRNA-independent pre-transfer editing activity for Nva, which is insufficient to remove mis-activated Nva. Moreover, hmtLeuRS chimeras fused with a functional CP1 domain from LeuRSs of other species, regardless of origin, showed restored post-transfer editing activity and acquired fidelity during aminoacylation. This work offers a novel perspective on the role of the CP1 domain in optimizing aminoacylation efficiency.     

The Role of Hemosiderin Excision in Seizure Outcome in Cerebral Cavernous Malformation Surgery: A Systematic Review and Meta-Analysis

Background and Purpose

Whether the excision of hemosiderin surrounding cerebral cavernous malformations (CCMs) is necessary to achieve a seizure-free result has been the subject of debate. Here, we report a systematic review of related literature up to Jan 1, 2015 including 594 patients to assess the effect of hemosiderin excision on seizure outcome in patients with CCMs by meta-analysis.

Methods

Ten studies comparing extended hemosiderin excision with only lesion resection were identified by searching the English-language literature. Meta-analyses, subgroup analyses and sensitivity analysis were conducted to determine the association between hemosiderin excision and seizure outcome after surgery.

Results

Seizure outcome was significantly improved in the patients who underwent an extended excision of the surrounding hemosiderin (OR, 0.62; 95% CI: 0.42–0.91; P = 0.01). In subgroup analysis, studies from Asia (OR, 0.42; 95% CI: 0.25–0.71; P = 0.001), male-majority (female ratio < 50%) studies (OR, 0.56; 95% CI: 0.33–0.96; P = 0.04), low occurrence rate of multiple CCMs (OR, 0.37; 95% CI: 0.20–0.71; P = 0.003), cohort studies (OR, 0.44; 95% CI: 0.28–0.68; P = 0.78), longer duration of seizure symptoms (> 1 year) before surgery (OR, 0.43; 95% CI: 0.22–0.84; P = 0.01), lesion diameter > 2 cm (OR, 0.41; 95% CI: 0.19–0.87; P = 0.02) and short-term (< 3 years) follow-up (OR, 0.48; 95% CI: 0.29–0.80; P = 0.005) tended to correlate with a significantly favorable outcome.

Conclusion

Patients who underwent extended surrounding hemosiderin excision could exhibit significantly improved seizure outcomes compared to patients without hemosiderin excision. However, further well-designed prospective multiple-center RCT studies are still needed.     

Effect of Tracheostomy on Weaning Parameters in Difficult-to-Wean Mechanically Ventilated Patients: A Prospective Observational Study

Background and Objective

Weaning parameters are commonly measured through an endotracheal tube in mechanically ventilated patients recovering from acute respiratory failure, however this practice has rarely been evaluated in tracheostomized patients. This study aimed to investigate changes in weaning parameters measured before and after tracheostomy, and to explore whether the data measured after tracheostomy were associated with weaning outcomes in difficult-to-wean patients.

Methods

In a two-year study period, we enrolled orotracheally intubated patients who were prepared for tracheostomy due to difficult weaning. Weaning parameters were measured before and after the conversion to tracheostomy and compared, and the post-tracheostomy data were tested for associations with weaning outcomes.

Results

A total of 86 patients were included. After tracheostomy, maximum inspiratory pressure (mean difference (Δ) = 4.4, 95% CI, 2.7 to 6.1, P<0.001), maximum expiratory pressure (Δ = 5.4, 95% CI, 2.9 to 8.0, P<0.001) and tidal volume (Δ = 33.7, 95% CI, 9.0 to 58.5, P<0.008) significantly increased, and rapid shallow breathing index (Δ = -14.6, 95% CI, -25.4 to -3.7, P<0.009) and airway resistance (Δ = -4.9, 95% CI, -5.8 to -4.0, P<0.001) significantly decreased. The patients who were successfully weaned within 90 days of the initiation of mechanical ventilation had greater increments in maximum inspiratory pressure (5.9 vs. 2.4, P = 0.04) and maximum expiratory pressure (8.0 vs. 2.0, P = 0.02) after tracheostomy than those who were unsuccessfully weaned.

Conclusions

In conclusion, the conversion from endotracheal tube to tracheostomy significantly improved the measured values of weaning parameters in difficult-to-wean patients who subsequently weaned successfully from the mechanical ventilator. The change was significant only for airway resistance in patients who failed weaning.

Trial Registration

ClinicalTrials.gov NCT01312142     

Assessment of HER2 Status Using Immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH) Techniques in Mucinous Epithelial Ovarian Cancer: A Comprehensive Comparison between ToGA Biopsy Method and ToGA Surgical Specimen Method

We aimed to compare the assay performance characteristics of HER2 status in mucinous epithelial ovarian cancer (EOC) by ToGA (Trastuzumab for Gastric Cancer) biopsy versus ToGA surgical specimen methods. Forty-nine tissue microarray (TMA) samples of mucinous EOC from Asian women were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests using ToGA trial HER2 scoring methods. The overall concordance between IHC and FISH by the ToGA surgical specimen method is 97.56% and by the ToGA biopsy specimen method is 97.14%. The agreements of HER2 IHC results under both biopsy and surgical specimen methods were nearly perfect (weighted kappa = 0.845). Additionally, the percentage of Her2 FISH amplification showed increasing trend with increasing HER2 IHC ordinals (negative, equivocal, positive) by both TOGA biopsy (P<0.001) and surgical specimen method (P<0.001). After excluding equivocal cases, the sensitivity (100%), PPV (88.89%) and NPV (100%) of HER2 IHC were unchanged under either surgical specimen method or biopsy method. However, the specificity (96.97%) and accuracy (97.56%) of HER2 IHC was slightly higher under the surgical specimen method than those (specificity 96.30%, accuracy 97.14%) under the biopsy method. Of the total 49 cases, the number (n = 14) of HER2 IHC equivocal results under the ToGA biopsy method was 1.75-fold higher than those (n = 8) under the ToGA surgical specimen method (28.57% vs. 16.32%). Therefore, compared to ToGA surgery specimen method, the ToGA biopsy method caused more equivocal IHC cases to be referred to FISH testing and did not increase the detection rates of Her2 FISH amplification.