Recent Updates in Cancer Immunotherapy: A Comprehensive Review and Perspective of the 2018 China Cancer Immunotherapy Workshop in Beijing

The immune system is the hard-wired host defense mechanism against pathogens as well as cancer. Five years ago, we pondered the question if the era of cancer immunotherapy was upon us (Li et al., Exp Hem Oncol 2013). Exciting progresses have been made at all fronts since then, including (1) sweeping approval of six agents by the US Food and Drug Administration (FDA) to block the PD-1/PD-L1 pathway for treatment of 13 cancer types; (2) a paradigm shifting indication of PD-1 and CTLA4 blockers for the management of a broad class of cancers with DNA mismatch repair defect, the first-ever tissue agnostic approval of cancer drugs; (3) real world practice of adoptive T cell therapy with two CD19-directed chimeric antigen receptor T cell products (CAR-T) for relapsed and/or refractory B cell malignancies including acute lymphoid leukemia and diffuse large B cell lymphoma, signaling the birth of a field now known as synthetic immunology; (4) the award of 2018 Nobel Prize in Physiology and Medicine from the Nobel Committee to Tasuku Honjo and James Allison for their discovery of cancer medicine by inhibition of negative immune regulation ( www.nobelprize.org/prizes/medicine/2018 ); and (5) the emerging new concept of normalizing rather than amplifying anti-tumor immunity for guiding the next wave of revolution in the field of immuno-oncology (IO) (Sanmamed and Chen, Cell 2018).This article will highlight the significant developments of immune-oncology as of October 2018. The US FDA approved indications of all seven immune checkpoint blockers, and two CD19-directed CAR-T products are tabulated for easy references. We organized our discussion into the following sections: introduction, cell therapy, emerging immunotherapeutic strategies, expediting oncology drug development in an era of breakthrough therapies, new concepts in cancer immunology and immunotherapy, and concluding remarks. Many of these topics were covered by the 2018 China Cancer Immunotherapy Workshop in Beijing, the fourth annual conference co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), China FDA (CFDA; now known as China National Medical Product Administration (NMPA)), and the Tsinghua University. We significantly expanded our discussion of important IO developments beyond what were covered in the conference, and proposed a new Three Rs conceptual framework for cancer immunotherapy, which is to reverse tolerance, rejuvenate the immune system, and restore immune homeostasis. We conclude that the future of immuno-oncology as a distinct discipline of cancer medicine has arrived

Celastrol nanoparticles inhibit corneal neovascularization induced by suturing in rats

Zhanrong Li1, Lin Yao1, Jingguo Li2, Wenxin Zhang1, Xianghua Wu1, Yi Liu1, Miaoli Lin1, Wenru Su1, Yongping Li1, Dan Liang11State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, 2School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, People's Republic of ChinaPurpose: Celastrol, a traditional Chinese medicine, is widely used in anti-inflammation and anti-angiogenesis research. However, the poor water solubility of celastrol restricts its further application. This paper aims to study the effect of celastrol nanoparticles (CNPs) on corneal neovascularization (CNV) and determine the possible mechanism.Methods: To improve the hydrophilicity of celastrol, celastrol-loaded poly(ethylene glycol)-block-poly(ε-caprolactone) nanopolymeric micelles were developed. The characterization of CNPs was measured by dynamic light scattering and transmission electron microscopy analysis. Celastrol loading content and release were assessed by ultraviolet-visible analysis and high performance liquid chromatography, respectively. In vitro, human umbilical vein endothelial cell proliferation and capillary-like tube formation were assayed. In vivo, suture-induced CNV was chosen to evaluate the effect of CNPs on CNV in rats. Immunohistochemistry for CD68 assessed the macrophage infiltration of the cornea on day 6 after surgery. Real-time quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were used to evaluate the messenger ribonucleic acid and protein levels, respectively, of vascular endothelial growth factor, matrix metalloproteinase 9, and monocyte chemoattractant protein 1 in the cornea.Results: The mean diameter of CNPs with spherical shape was 48 nm. The celastrol loading content was 7.36%. The release behavior of CNPs in buffered solution (pH 7.4) showed a typical two-phase release profile. CNPs inhibited the proliferation of human umbilical vein endothelial cells in a dose-independent manner and suppressed the capillary structure formation. After treatment with CNPs, the length and area of CNV reduced from 1.16 ± 0.18 mm to 0.49 ± 0.12 mm and from 7.71 ± 0.94 mm2 to 2.29 ± 0.61 mm2, respectively. Macrophage infiltration decreased significantly in the CNP-treated corneas. CNPs reduced the expression of vascular endothelial growth factor, matrix metalloproteinase 9, and monocyte chemoattractant protein 1 in the cornea on day 6 after suturing.Conclusion: CNPs significantly inhibited suture-induced CNV by suppressing macrophage infiltration and the expression of vascular endothelial growth factor and matrix metalloproteinase 9 in the rat cornea.Keywords: celastrol, PEG-b-PCL nanopolymeric micelles, corneal neovascularization, macrophages, VEGF, MMP-

Pilot Study on Image Quality and Radiation Dose of CT Colonography with Adaptive Iterative Dose Reduction Three-Dimensional

Objective: To investigate image quality and radiation dose of CT colonography (CTC) with adaptive iterative dose reduction three-dimensional (AIDR3D). Methods: Ten segments of porcine colon phantom were collected, and 30 pedunculate polyps with diameters ranging from 1 to 15 mm were simulated on each segment. Image data were acquired with tube voltage of 120 kVp, and current doses of 10 mAs, 20 mAs, 30 mAs, 40 mAs, 50 mAs, respectively. CTC images were reconstructed using filtered back projection (FBP) and AIDR3D. Two radiologists blindly evaluated image quality. Quantitative evaluation of image quality included image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). Qualitative image quality was evaluated with a five-score scale. Radiation dose was calculated based on dose-length product. Ten volunteers were examined supine 50 mAs with FBP and prone 20 mAs with AIDR3D, and image qualities were assessed. Paired t test was performed for statistical analysis. Results: For 20 mAs with AIDR3D and 50 mAs with FBP, image noise, SNRs and CNRs were (16.4 ± 1.6) HU vs. (16.8 ± 2.6) HU, 1.9 ± 0.2 vs. 1.9 ± 0.4, and 62.3 ± 6.8 vs. 62.0 ± 6.2, respectively; qualitative image quality scores were 4.1 and 4.3, respectively; their differences were all not statistically significant. Compared with 50 mAs with FBP, radiation dose (1.62 mSv) of 20 mAs with AIDR3D was decreased by 60.0%. There was no statistically significant difference in image noise, SNRs, CNRs and qualitative image quality scores between prone 20 mAs with AIDR3D and supine 50 mAs with FBP in 10 volunteers, the former reduced radiation dose by 61.1%. Conclusion: Image quality of CTC using 20 mAs with AIDR3D could be comparable to standard 50 mAs with FBP, radiation dose of the former reduced by about 60.0% and was only 1.62 mSv

Deficiency of Brummer Impaires Lipid Mobilization and JH-Mediated Vitellogenesis in the Brown Planthopper, Nilaparvata lugens

Provisioning of sufficient lipids and vitellogenin to the oocytes is an indispensable process for fecundity of oviparous insects. Acute mobilization of lipid reserves in insects is controlled by the Brummer (Bmm), an orthologous of human adipose triglyceride lipase (ATGL). To investigate the functional roles of brummer-mediated lipolysis in the fecundity of the brown planthopper, Nilaparvata lugens, RNA interference (RNAi) analyses were performed with double-stranded RNA (dsRNA) against NlBmm in adult females. Knockdown of NlBmm expression resulted in obesity and blocked lipid mobilization in the fat body. In addition, NlBmm silencing led to retarded ovarian development with immature eggs and less ovarioles, decreased number of laid eggs, prolonged preoviposition period and egg duration. Furthermore, severe reductions of vitellogenin and its receptor abundance were observed upon NlBmm knockdown. The transcript levels of NlJHE (juvenile hormone esterase) which degrades JH were up-regulated, whereas the expression levels of JH receptors NlMet (Methoprene-tolerant) and NlTai (Taiman) and their downstream transcription factors NlKr-h1 (Krüppel-homolog 1) and NlBr (Broad-Complex) were down-regulated after suppression of NlBmm. JH-deficient females exhibited impaired vitellogenin expression, whereas JH exposure stimulated vitellogenin biosynthesis. Moreover, JH topical application partially rescued the decrease in vitellogenin expression in the NlBmm-deficient females. These results demonstrate that brummer-mediated lipolytic system is essential for lipid mobilization and energy homeostasis during reproduction in N. lugens. In addition to the classical view of brummer as a direct lipase with lipolysis activity, we propose here that brummer-mediated lipolysis works through JH signaling pathway to activate vitellogenesis and oocyte maturation that in turn regulates female fecundity

The Efficacy of Adalimumab as an Initial Treatment in Patients with Behçet’s Retinal Vasculitis

Background: No study has evaluated the effectiveness of Adalimumab (ADA) as first-line in treatment-naïve patients with retinal vasculitis due to Behçet’s Uveitis (BU).Objective: To compare the efficacy of ADA plus conventional therapy and conventional therapy alone as initial treatments in naïve BU patients characterized by retinal vasculitis.Methods: Medical records of BU patients characterized by retinal vasculitis treated with conventional therapy (CT, refers to glucocorticoid and immunosuppressive agents) alone or ADA plus conventional therapy with at least 6 months of follow-up between February 2015 and June 2020 were analyzed. Only patients who were first diagnosed with BU without previous systemic treatment were reviewed. The retinal vasculitis score based on fluorescein angiography (FA), best-corrected visual acuity, glucocorticoid-sparing effect, the number of relapses and ocular complications were evaluated.Results: A total of 45 patients (87 eyes) were included. Twenty-four patients (55.33%) in the CT group were treated with conventional therapy and 21 patients (46.67%) in the ADA group were treated with ADA plus conventional therapy. The inflammatory parameters improved in both groups. FA scores showed significantly greater improvement in ADA group than CT group (p < 0.001). The median number of relapses was significantly lower, and the duration of remission was longer in ADA group than CT group (p < 0.001). At the last visit, a significantly better BCVA improvement (p = 0.024), better inflammation control (anterior chamber inflammation p = 0.017 and vitritis p < 0.001) and lower daily glucocorticoid dosage (p = 0.005) were identified in patients received ADA therapy. In CT group, 1 patient suffered hepatitis B and tuberculosis, 1 had growth retardation, 1 patient had with osteoporosis, then followed by other mild AEs (mostly respiratory upper tract infections); while in ADA group, 1 patient experienced a mild pneumonia (n = 1) while milder AEs were represented mostly by respiratory upper tract infections followed by gastrointestinal discomfort.Conclusion: ADA plus conventional therapy achieved superiority over conventional therapy as initial treatment in naïve BU patients with retinal vasculitis

Adipokinetic Hormone Receptor Mediates Trehalose Homeostasis to Promote Vitellogenin Uptake by Oocytes in Nilaparvata lugens

Adipokinetic hormones (AKHs) are well known to mobilize lipids and carbohydrates for energy-consuming activities in insects. These neuropeptides exert their functions by interacting with AKH receptors (AKHRs) located on the plasma membrane of fat body cells, which regulates energy mobilization by stimulating lipolysis of triacylglycerols (TAG) to diacylglycerols (DAG) and conversion of glycogen into trehalose. Here, we investigated the roles of AKH/AKHR signaling system in trehalose metabolism and vitellogenesis during female reproduction in the brown planthopper, Nilaparvata lugens. Knockdown of AKHR expression by RNA interference (RNAi) resulted in a decrease of the circulating trehalose in hemolymph and significantly increased levels of two trehalases in fat bodies, indicating that the modulation of hemolymph trehalose levels by AKHR may be mediated by regulating trehalose degradation. In addition, adult females that had been injected with double-stranded RNA (dsRNA) for AKHR exhibited delayed oocyte maturation, prolonged pre-oviposition period, as well as decline in egg number and reduction in fecundity. Considering that these phenotypes resulting from AKHR silencing are similar to those of vitellogenin receptor (VgR) RNAi, we further analyzed a possible connection between AKHR and vitellogenesis. Knockdown of AKHR showed no effects on the Vg synthesis in fat bodies, whereas it significantly reduced the levels of VgR in ovaries. With RNAi-females, we observed an increase of Vg accumulation in hemolymph and a decrease of Vg deposition in ovaries. Moreover, the decrease in VgR expression and Vg incorporation by developing oocytes could be partially rescued by injection of trehalose into AKHR RNAi females. The present study has implicated trehalose in the AKH/AKHR signaling-mediated control of reproduction and provided new insight into mechanisms of AKH/AKHR regulation of trehalose metabolism in insect vitellogenesis, oocyte maturation and fecundity

A piggyBac transposon-based mutagenesis system for the fission yeast Schizosaccharomyces pombe

The TTAA-specific transposon piggyBac (PB), originally isolated from the cabbage looper moth, Trichoplusia ni, has been utilized as an insertional mutagenesis tool in various eukaryotic organisms. Here, we show that PB transposes in the fission yeast Schizosaccharomyces pombe and leaves almost no footprints. We developed a PB-based mutagenesis system for S. pombe by constructing a strain with a selectable transposon excision marker and an integrated transposase gene. PB transposition in this strain has low chromosomal distribution bias as shown by deep sequencing-based insertion site mapping. Using this system, we obtained loss-of-function alleles of klp5 and klp6, and a gain-of-function allele of dam1 from a screen for mutants resistant to the microtubule-destabilizing drug thiabendazole. From another screen for cdc25-22 suppressors, we obtained multiple alleles of wee1 as expected. The success of these two screens demonstrated the usefulness of this PB-mediated mutagenesis tool for fission yeast

RETRATO SIN IDENTIFICAR [Material gráfico]

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte, 201