Anti-HIV drugs lopinavir/ritonavir activate bitter taste receptors.

Lopinavir and ritonavir (LPV/r) are the primary anti-human immunodeficiency virus (HIV) drugs recommended by the World Health Organization for treating children aged 3 years and above who are infected with the HIV. These drugs are typically available in liquid formulations to aid in dosing for children who cannot swallow tablets. However, the strong bitter taste associated with these medications can be a significant obstacle to adherence, particularly in young children, and can jeopardize the effectiveness of the treatment. Studies have shown that poor palatability can affect the survival rate of HIV-infected children. Therefore, developing more child-friendly protease inhibitor formulations, particularly those with improved taste, is critical for children with HIV. The molecular mechanism by which lopinavir and ritonavir activate bitter taste receptors, TAS2Rs, is not yet clear. In this study, we utilized a calcium mobilization assay to characterize the activation of bitter taste receptors by lopinavir and ritonavir. We discovered that lopinavir activates TAS2R1 and TAS2R13, while ritonavir activates TAS2R1, TAS2R8, TAS2R13, and TAS2R14. The development of bitter taste blockers that target these receptors with a safe profile would be highly desirable in eliminating the unpleasant bitter taste of these anti-HIV drugs.

Structural and magnetic properties of Y3(GaAlFe)5O12 liquid-phase epitaxy films with low ferromagnetic resonance losses.

Ultra-thin rare earth iron garnet (RIG) films with a narrow ferromagnetic resonance (FMR) line width and a low damping factor have attracted a great deal of attention for microwave and spintronic applications. In this work, 200 nm Y3(GaAlFe)5O12 garnet (GaAl-YIG) films were prepared on gadolinium gallium garnet (GGG) substrates by liquid-phase epitaxy (LPE) with low saturation magnetization. The microstructural properties, chemical composition, and magnetostatic and dynamic magnetization characteristics of the films are discussed in detail. According to the structural analysis, these films exhibit a low surface roughness of less than 0.5 nm. The GaAl-YIG films show an obvious temperature dependence of lattice parameter and strain state, and the film's parameter is perfectly matched with that of the GGG substrate at 810°C. There is a clear variation in the Pb level, which brings about a gradual enhancement of the coercivity and a diminution of the squareness ratio of magnetic hysteresis loops as the growth temperature is reduced. Slight changes in surface roughness, strain condition and content of Pb induce the FMR line width and damping factor to vary on a small scale. The line width is less than 10.17 Oe at 12 GHz and the damping factor is of the order of 10-4. All these properties demonstrate that these ultra-thin GaAl-YIG films are of benefit for the development of devices operated at lower frequencies and in lower fields.

Antibody-dependent cell-mediated cytotoxicity using T cells with NK-like phenotype in combination with avelumab, an anti-PD-L1 antibody.

Though the PD-L1 checkpoint inhibitor avelumab has shown efficacy in the treatment of some types of cancer, improved treatment strategies are desperately needed. We evaluated whether combined treatment with avelumab and adoptively transferred T-NK cells can provide enhanced anti-cancer effects for treating PD-L1-expressing tumours. Our results demonstrate that avelumab specifically targets tumour cells with high PD-L1 expression, and that cytolytic effects are mediated by T-NK effector cells cultured from patient peripheral blood monocytic cell populations. The effects were dependent on CD16 and the perforin/granzyme pathway, supporting a role for the T-NK subpopulation. In vivo assays verified the efficacy of T-NK cells in combination with avelumab in reducing tumour growth. Furthermore, T-NK + avelumab prolonged survival in a mouse orthotopic xenograft model. Collectively, our findings provide a basis for the combined use of adoptively transferred T-NK cells with avelumab as a novel strategy for cancer treatment.

Dual-band terahertz all-silicon metasurface with giant chirality for frequency-undifferentiated near-field imaging.

Chiral metasurfaces are widely used in imaging and biosensing due to their powerful light field control capabilities. Most of the work is devoted to achieving the goals of chirality enhancement and tunability, but lacks consideration of design complexity, loss, cost, and multi-band operation. In order to alleviate this situation, we propose a pair of dual-frequency giant chiral structures based on all-silicon, which can achieve excellent and opposite spin-selective transmission around 1.09 THz and 1.65 THz. The giant chirality derives from the in-plane electric and magnetic dipole moments excited in different degrees. Theoretically, the maximum circular dichroism at the two frequencies are both as high as 0.34, and the coverage bandwidths of the two giant chirality are 85.5 GHz and 41.4 GHz, respectively. The experimental results are in good agreement with the simulation results. Based on the dual-band giant chiral patterns, the terahertz near-field imaging of different Chinese character images is demonstrated at two frequencies. The frequency-undifferentiated characteristics, good intensity contrast and three-dimensional imaging information are shown by the results. This work provides new ideas for the design of terahertz devices with simple structure and multi-functions, which are expected to be applied in the field of terahertz imaging or multi-channel communication.

IL-15-induced lymphocytes as adjuvant cellular immunotherapy for gastric cancer.

Objectives To test the antitumor potential of lymphocytes transferred via adoptive cell therapy (ACT) in a mouse model of human gastric cancer (GC), and to evaluate the clinical efficacy and safety of combining lymphocytes as adjuvant therapy with first-line chemotherapy in patients with GC. Methods We constructed a human GC xenograft model in sublethally irradiated 6-8-week-old male NCG mice. MKN-45 cells (1 × 106 cells/mouse) were subcutaneously injected into mice's flanks. After tumors had become palpable, we randomized the mice into control, ACTIL-2, and ACTIL-15 groups. Human lymphocytes were then injected into mouse tail veins. In addition, 63 human patients with histologically or cytologically confirmed stage III-IV GC randomly received S-1 + oxaliplatin + ACTIL-15 (combination therapy group) or S-1 + oxaliplatin (chemotherapy group). Results In the mouse study, treatment with ACTIL-15 cells inhibited tumor growth on adoptive transfer, and mice that received ACTIL-15 cells had significantly longer survival rates (p < 0.05, ACTIL-15 vs. ACTIL-2). In the human study, the median survival rate of patients in the combination therapy group was 472 days (95% confidence interval [CI], 276-668 days), whereas that of patients in the chemotherapy group was 266 days (95% CI, 200-332 days; p < 0.05). Eleven percent (7/63) of patients had adverse reactions, but these reactions did not interfere with treatment. Conclusion Adoptive transfer of ACTIL-15 cells in a mouse model of GC and in patients with advanced GC treated with S1 + oxaliplatin improved survival rates in both, with an acceptable safety profile.

Synergistic effect of adoptive immunotherapy and docetaxel inhibits tumor growth in a mouse model.

Adoptive T cell transfer therapy (ACT) has emerged as a promising approach to cancer immunotherapy; however, the efficacy of ACT is limited by the T-cell suppressive activity of myeloid-derived suppressor cells (MDSCs), which accumulate in the tumor microenvironment after ACT. We sought to determine whether the efficacy of ACT could be enhanced by co-treatment with docetaxel, a taxane chemotherapy agent that has been shown previously to inhibit MDSC function. Using a mouse tumor model, we demonstrated that ACT and docetaxel synergistically inhibit the growth either of engrafted CT26 colon cancer or 4T1 mammary carcinoma cells. While ACT mediated an increase in the recruitment of MDSCs to the site of the tumor, docetaxel reversed this increase. Furthermore, ex vivo cultures of tumor-associated MDSCs suppressed the cytotoxic activity of tumor-specific T cells, and this suppressive activity was abolished by docetaxel treatment. These results suggest that docetaxel inhibits both the tumor recruitment and T cell suppressive activity of MDSCs. Inhibitors of iNOS and arginase partially inhibited ex vivo MDSC activity, and combined inhibition of iNOS and arginase had a similar effect as docetaxel, which supports the possibility that docetaxel may function by inhibiting ACT-associated activation of these pathways. Furthermore, docetaxel mediated inhibition of the T cell suppressive activity of MDSCs from human blood, which supports the potential clinical applicability of these findings. On the basis of these findings, docetaxel treatment may represent an effective therapeutic approach for reversing immunosuppression by MDSCs subsequent to ACT-based therapy.

[Clinical evaluation of restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis].

OBJECTIVE: To evaluate the clinical efficacies of restorative proctocolectomy with ileal pouch-anal anastomosis (RP-IPAA) for ulcerative colitis (UC). METHODS: A total of 115 UC patients underwent the procedure of RP-IPAA during the period of 1989 to 2010. The data of surgical procedures, complications and long-term outcomes were collected. Stool frequency during the 24-hour period and the night were recorded at months 3 and 12 post-operation. Anal continence functions were evaluated by the Kirwan grading scale and the fecal characteristics identified by Bristol stool form scale. The patients' quality of life was objectively accessed by the Cleveland Global Quality of Life (CGQL) index. RESULTS: No perioperative death was reported. The mean follow-up period was for at least 12 months. The postoperative complication rate was 20.9% (24/115), including infectious complications, wound infection and(or) abdominal abscess, anastomotic leak, pouch hemorrhage, pouch-vaginal fistula, pouchitis, terminal proctitis, urinary calculi and male sexual dysfunctions. Stool frequency per 24 hours and night was < 3 to 12 month post-operation (3.9 ± 1.7 vs 6.1 ± 2.6, 1.3 ± 0.7 vs 2.8 ± 1.8, both P < 0.05). No significant changes in anal continence functions existed between the above two time points [Grade I: 87.0% (n = 100) vs 92.2% (n = 106), Grade II: 7.8% (n = 9) vs 4.3% (n = 5), Grade III: 5.2% (n = 6) vs 3.5% (n = 4), all P > 0.05]. The postoperative CGQL results showed a much better quality of life than preoperative one. CONCLUSION: As the first-choice operation for UC, RP-IPAA is safe and it offers satisfactory long-term outcomes and improved quality of life.

Crystal structure of human phosphoribosylpyrophosphate synthetase 1 reveals a novel allosteric site.

PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. The enzymatic activity of PRS is regulated by phosphate ions, divalent metal cations and ADP. In the present study we report the crystal structures of recombinant human PRS1 in complexes with SO4(2-) ions alone and with ATP, Cd2+ and SO4(2-) ions respectively. The AMP moiety of ATP binds at the ATP-binding site, and a Cd2+ ion binds at the active site and in a position to interact with the beta- and gamma-phosphates of ATP. A SO4(2-) ion, an analogue of the activator phosphate, was found to bind at both the R5P-binding site and the allosteric site defined previously. In addi-tion, an extra SO4(2-) binds at a site at the dimer interface between the ATP-binding site and the allosteric site. Binding of this SO4(2-) stabilizes the conformation of the flexible loop at the active site, leading to the formation of the active, open conformation which is essential for binding of ATP and initiation of the catalytic reaction. This is the first time that structural stabilization at the active site caused by binding of an activator has been observed. Structural and biochemical data show that mutations of some residues at this site influence the binding of SO4(2-) and affect the enzymatic activity. The results in the present paper suggest that this new SO4(2-)-binding site is a second allosteric site to regulate the enzymatic activity which might also exist in other eukaryotic PRSs (except plant PRSs of class II), but not in bacterial PRSs.

The MRG domain of human MRG15 uses a shallow hydrophobic pocket to interact with the N-terminal region of PAM14.

MRG15 is a transcription factor expressed in a variety of human tissues, and its orthologs have been found in many other eukaryotes which constitute the MRG protein family. It plays a vital role in embryonic development and cell proliferation, and is involved in cellular senescence. The C-terminal part of MRG15 forms a conserved MRG domain which is involved in interactions with the tumor suppressor protein retinoblastoma and a nucleoprotein PAM14 during transcriptional regulation. We report here the characterization of the interaction between the MRG domain of human MRG15 and PAM14 using both yeast two-hybrid and in vitro binding assays based on the crystal structure of the MRG domain. The MRG domain is predominantly hydrophobic, and consists of mainly alpha-helices that are arranged in a three-layer sandwich topology. The hydrophobic core is stabilized by interactions among a number of conserved hydrophobic residues. The molecular surface is largely hydrophobic, but contains a few hydrophilic patches. Structure-based site-directed mutagenesis studies identified key residues involved in the binding of PAM14. Structural and biochemical data together demonstrate that the PAM14 binding site is consisted of residues Ile160, Leu168, Val169, Trp172, Tyr235, Val268, and Arg269 of MRG15, which form a shallow hydrophobic pocket to interact with the N-terminal 50 residues of PAM14 through primarily hydrophobic interactions. These results provide the molecular basis for the interaction between the MRG domain and PAM14, and reveal insights into the potential biological function of MRG15 in transcription regulation and chromatin remodeling.