New York-esophageal cancer 1 (NY-ESO-1) belongs to the cancer testis antigen (CTA) family, and has been identified as one of the most immunogenic tumor-associated antigens (TAAs) among the family ...members. Given its ability to trigger spontaneous humoral and cellular immune response and restricted expression, NY-ESO-1 has emerged as one of the most promising targets for cancer immunotherapy. Cancer vaccines, an important element of cancer immunotherapy, function by presenting an exogenous source of TAA proteins, peptides, and antigenic epitopes to CD4
+
T cells
via
major histocompatibility complex class II (MHC-II) and to CD8
+
T cells
via
major histocompatibility complex class I (MHC-I). These mechanisms further enhance the immune response against TAAs mediated by cytotoxic T lymphocytes (CTLs) and helper T cells. NY-ESO-1-based cancer vaccines have a history of nearly two decades, starting from the first clinical trial conducted in 2003. The current cancer vaccines targeting NY-ESO-1 have various types, including Dendritic cells (DC)-based vaccines, peptide vaccines, protein vaccines, viral vaccines, bacterial vaccines, therapeutic whole-tumor cell vaccines, DNA vaccines and mRNA vaccines, which exhibit their respective benefits and obstacles in the development and application. Here, we summarized the current advances in cancer vaccines targeting NY-ESO-1 for solid cancer treatment, aiming to provide perspectives for future research.
Abstract Background context Compared with conventional microsurgical technique, the full endoscopic (FE) interlaminar approach is a more minimally invasive technique for the surgical treatment of ...lumbar disc herniations. Its efficacy and safety have been confirmed by numerous studies. However, a steep learning curve with the use of such a complex technique is a major concern for the initial adoption of this technique. Purpose To evaluate the learning curve of using an FE interlaminar technique for the surgical treatment of lumbar disc herniation. Study design A prospective study of patients with lumbar disc herniation who underwent discectomy via interlaminar approach assisted by FE instruments. Patient sample Thirty patients with lumbar disc herniation underwent discectomy using an interlaminar endoscopic-only approach between 2008 and 2009. Methods The patients were divided into three groups of 10 sequential cases each. Group A consisted of the first 10 cases, Group B the subsequent 10 cases, and Group C the last 10 cases. The clinical evaluation data included operative time, length of hospital stay, visual analog scale (VAS) leg and back pain scores, complications, and rate of conversion to an open. Results All patients were observed prospectively for 1.61±0.22 years (range, 1.2–2.0 years). There was no measurable intraoperative bleeding and postoperative infections in the three groups. Compared with Group A, the operative time in Group B was significantly decreased (p<.001). The patients in Group C had much less operative time than in Group B (p=.002). There was no significant difference with length of hospital stay in the three groups (p=.897). The improvement of VAS leg and back pain scores in each group was similar: there was a significant improvement (p<.01) at 3 months after surgery when compared with preoperative scores, but there was no statistical difference (p>.05) in the VAS leg and back pain scores between 3 months after surgery and final follow-up. The complication rate was 12.5% for Group A, 10% for Group B, and 0% for Group C. The need for conversion to an open procedure for Group A was 20% compared with zero cases in both Groups B and C. There were no symptomatic recurrences in our study. Conclusions Excellent clinical and minimally invasive outcomes can be obtained in the surgical treatment of lumbar disc herniation via the interlaminar approach assisted by FE technique. However, attention must be paid to the steep learning curve by using this complex technique. Imprecise anatomic orientation and manipulation inside the spinal canal are key factors in the steep learning curve. Obtaining microsurgical experience, attending workshops, and suitable patient selection can help shorten the learning curve and decrease the complications.
Combination therapy has been widely explored for oncolytic virus (OV), as it can be met with tumor resistance. The HDAC inhibitor (HDACi) panobinostat is a potent pan-deacetylase inhibitor which ...blocks multiple cancer-related pathways and reverses epigenetic events in cancer progression.
In this study, oncolytic activity in vitro and antitumor therapeutic efficacy in vivo when combined with oHSV and panobinostat were investigated.
(1) Treatment with panobinostat enhanced oHSV propagation and cytotoxicity in human glioma A172 and squamous cell carcinoma SCC9 cells. (2) Combined treatment with oHSV and panobinostat enhanced virus replication mediated by the transcriptional downregulation of IFN-β- and IFN-responsive antiviral genes in human glioma A172 and squamous cell carcinoma SCC9 cells. (3) Panobinostat treatment induced upregulation of PD-L1 expression in both glioma and squamous cell carcinoma cells. (4) A significantly enhanced therapeutic efficacy was shown in vivo for the murine glioma CT-2A and squamous cell carcinoma SCC7 models when treated with a combination of oHSV, including PD-1/PD-L1 blockade and HDAC inhibition.
Consequently, these data provide some new clues for the clinical development of combination therapy with OVs, epigenetic modifiers, and checkpoint blockades for glioma and squamous cell carcinoma.
Cranial radiation therapy is one of the most effective treatments for childhood brain cancers. Despite the ameliorated survival rate of juvenile patients, radiation exposure-induced brain neurogenic ...region injury could markedly impair patients' cognitive functions and even their quality of life. Determining the mechanism underlying neural stem cells (NSCs) response to irradiation stress is a crucial therapeutic strategy for cognitive impairment. The present study demonstrated that X-ray irradiation arrested NSCs' cell cycle and impacted cell differentiation. To further characterize irradiation-induced molecular alterations in NSCs, two-dimensional high-resolution mass spectrometry-based quantitative proteomics analyses were conducted to explore the mechanism underlying ionizing radiation's influence on stem cell differentiation. We observed that ionizing radiation suppressed intracellular protein transport, neuron projection development, etc., particularly in differentiated cells. Redox proteomics was performed for the quantification of cysteine thiol modifications in order to profile the oxidation-reduction status of proteins in stem cells that underwent ionizing radiation treatment. Via conjoint screening of protein expression abundance and redox status datasets, several significantly expressed and oxidized proteins were identified in differentiating NSCs subjected to X-ray irradiation. Among these proteins, succinate dehydrogenase ubiquinone flavoprotein subunit, mitochondrial (sdha) and the acyl carrier protein, mitochondrial (Ndufab1) were highly related to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease, illustrating the dual-character of NSCs in cell differentiation: following exposure to ionizing radiation, the normal differentiation of NSCs was compromised, and the upregulated oxidized proteins implied a degenerative differentiation trajectory. These findings could be integrated into research on neurodegenerative diseases and future preventive strategies.
This work aimed to evaluate the effects of genistein treatment in Collagen Induced Arthritis (CIA) mouse model.
CIA was elicited in DBA/1 Mice by an intradermal injection of 100 μL of an emulsion of ...bovine type II collagen (CII) in isovolumic incomplete Freund's adjuvant (IFA) at the base of the tail. Twenty-one days later, a second injection of CII in IFA was administered at the base of the tail. After the symptoms of arthritis showed in mouse model, we divided animals into two groups according to their clinical symptom scores. The treatment group was intraperitoneally injected daily with genistein (based on the pre-experiment data and literature reported, 5 mg/kg dose was selected and tested) for 12 days, while the control group was injected with phosphate buffered saline. Inflammatory cytokines titer, radiological, and histological observations were completed at different time's points after treatment. CT analysis was conducted 3 months after the treatment to observe the articular structures. Immunohistochemical analysis was performed to investigate the expression and distribution of VEGF in joint tissues.
Genistein suppressed the expressions of IL-1β, IL-6 and TNF-α in the serum. Radiological results showed that bone degradation was inhibited by the treatment. Moreover, hematoxylin and eosin staining showed that the degree of inflammation was relieved. In the cartilage area, TRAP stain-positive cells were detected, which was notably reduced in the treatment group compared to the control group. Micro-CT 3D images clearly exhibited that the joint adhered and structures destroyed in the control group with less destruction in the treatment group. Furthermore, genistein suppressed VEGF expression, and blocked angiogenesis in the synovial tissue.
Our work provides further data regarding the effects of genistein as a potential treatment drug for RA, as well as the role of genistein in the anti-inflammatory pathway in RA therapy.
As a multifaceted adipokine, chemerin has been found to perform functions vital for immunity, adiposity, and metabolism through its three known receptors (chemokine-like receptor 1, CMKLR1; ...G-protein-coupled receptor 1, GPR1; C-C motif chemokine receptor-like 2, CCRL2). Chemerin and the cognate receptors are also expressed in the hypothalamus, pituitary gland, testis, ovary, and placenta. Accumulating studies suggest that chemerin participates in normal reproduction and underlies the pathological mechanisms of certain reproductive system diseases, including polycystic ovary syndrome (PCOS), preeclampsia, and breast cancer. Herein, we present a comprehensive review of the roles of the chemerin system in multiple reproductive processes and human reproductive diseases, with a brief discussion and perspectives on future clinical applications.
A Gram-positive, halophilic bacterium was isolated from a sediment sample from Ai-Ding salt lake in China. The isolate, designated strain 17-5(T), grew at salinities of 8-33 % (w/v) NaCl (optimally ...at 12 %, w/v). The genomic DNA G+C content of strain 17-5(T) was 48.1 mol%. The predominant isoprenoid quinone was MK-7(H(2)) and the cell-wall peptidoglycan contained meso-diaminopimelic acid. The major polar lipids were diphosphatidylglycerol and an unidentified glycolipid. The major cellular fatty acids were anteiso-C(15 : 0), anteiso-C(17 : 0), iso-C(16 : 0) and C(16 : 0). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain 17-5(T) was a member of the genus Bacillus, being most closely related to Bacillus qingdaonensis JCM 14087(T) (96.0 % sequence similarity) and Bacillus salarius DSM 16461(T) (95.6 %). The levels of 16S rRNA gene sequence similarity with respect to other Bacillus species were less than 91.7 %. Comparative analysis of the 16S rRNA gene sequence data, chemotaxonomy and phenotypic features of the novel isolate and related species of Bacillus indicated that strain 17-5(T) represents a novel species within the genus Bacillus, for which the name Bacillus aidingensis sp. nov. is proposed. The type strain is 17-5(T) (=CGMCC 1.3227(T)=DSM 18341(T)).
Placental dysfunction underlies numerous complications of pregnancy. A major obstacle to understanding the roles of potential mediators of placental pathology has been the absence of suitable methods ...for tissue-specific gene manipulation and sensitive assays for studying gene functions in the placentas of intact animals. We describe a sensitive and noninvasive method of repetitively tracking placenta-specific gene expression throughout pregnancy using lentivirus-mediated transduction of optical reporter genes in mouse blastocysts.
Zona-free blastocysts were incubated with lentivirus expressing firefly luciferase (Fluc) and Tomato fluorescent fusion protein for trophectoderm-specific infection and transplanted into day 3 pseudopregnant recipients (GD3). Animals were examined for Fluc expression by live bioluminescence imaging (BLI) at different points during pregnancy, and the placentas were examined for tomato expression in different cell types on GD18. In another set of experiments, blastocysts with maximum photon fluxes in the range of 2.0E+4 to 6.0E+4 p/s/cm(2)/sr were transferred. Fluc expression was detectable in all surrogate dams by day 5 of pregnancy by live imaging, and the signal increased dramatically thereafter each day until GD12, reaching a peak at GD16 and maintaining that level through GD18. All of the placentas, but none of the fetuses, analyzed on GD18 by BLI showed different degrees of Fluc expression. However, only placentas of dams transferred with selected blastocysts showed uniform photon distribution with no significant variability of photon intensity among placentas of the same litter. Tomato expression in the placentas was limited to only trophoblast cell lineages.
These results, for the first time, demonstrate the feasibility of selecting lentivirally-transduced blastocysts for uniform gene expression in all placentas of the same litter and early detection and quantitative analysis of gene expression throughout pregnancy by live BLI. This method may be useful for a wide range of applications involving trophoblast-specific gene manipulations in utero.
The liver is an essential multifunctional organ, which constantly communicates with nearly all tissues. It has raised the concern that microgravity exposure can lead to liver dysfunction and ...metabolic syndromes. However, molecular mechanisms and intervention measures of the adverse effects of microgravity on hepatocytes are limited. In this study, we utilized the random positioning machine culture system to investigate the adverse effects on hepatocytes under simulated microgravity (SMG). Our results showed that SMG impaired hepatocyte viability, causing cell cycle arrest and apoptosis. Compared to normal gravity, it also triggered lipid accumulation, elevated triglyceride (TG) and ROS levels, and impaired mitochondria function in hepatocytes. Furthermore, RNA sequencing results showed that SMG upregulated genes implicated in lipid metabolisms, including PPARγ, PLIN2, CD36, FABPs, etc. Importantly, all these defects can be suppressed by melatonin, a potent antioxidant secreted by the pineal gland, suggesting its potential use of therapeutic intervention.
Melatonin reduces SMG‐induced cellular ROS production, restores mitochondria respiration, and suppresses the expression of genes involved in TG synthesis, e.g., PPARγ and PLIN2, thereby reducing lipid droplet formation. In addition, it suppresses fatty acid intake, down‐regulates FABPs and CD36, mitigates apoptosis, and reduces CPT1a. Hence, the antioxidative effect of melatonin mitigates SMG‐mediated detrimental effects in hepatocytes.
Allografts are important alternatives to autografts for treating defects after major bone loss. Bone growth factors have both local autocrine and paracrine effects and regulate the growth, ...proliferation, and differentiation of osteoprogenitor cells. To study the effects of prolonged, continuous, local delivery of growth factors on bone growth, we developed a new microelectromechanical system (MEMS) drug delivery device. Bone marrow cells from mice were seeded on mouse allograft discs and cultured in osteogenic media with osteogenic protein 1 (OP-1) and/or basic fibroblast growth factor (FGF-2) delivered from MEMS devices for 6 weeks. We monitored bone formation by changes of bone volume using micro-CT scanning and release of osteocalcin using ELISA. The data suggest the MEMS devices delivered constant concentrations of OP-1 and FGF-2 to the media. Bone marrow cells grew on the allografts and increased bone volume. Addition of OP-1 increased bone formation whereas FGF-2 decreased bone formation. Local delivery of growth factors over a prolonged period modulated the differentiation of osteoprogenitor cells on allograft bone.
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