Search

Nanodynamic therapy (NDT) based on reactive oxygen species (ROS) production has been envisioned as an effective cancer treatment. However, the efficacy is limited by the hypoxia, insufficient hydrogen peroxide conversion, and high glutathione (GSH) levels in the tumor microenvironment (TME). To solve these issues, we proposed and designed a biocompatible, oxygen resistant Cu-modified Ti3C2 nanocomposite (Ti3C2-Cu-PEG), which can efficiently deplete the endogenous GSH in tumor cells, smartly respond to NIR-II light irradiation with in-depth tissue penetration to achieve photothermally enhanced tumor photodynamic therapy (PDT) and catalytic therapy. Specifically, Ti3C2-Cu-PEG reacted with oxygen to produce singlet oxygen (1O2) under NIR-II irradiation, and catalyzed the highly expressed H2O2 in the tumor microenvironment to generate ·OH. In addition, Ti3C2-Cu-PEG significantly decreased intracellular GSH, reduced the chances of reaction between ROS and GSH, and thus promoting ROS effect. Moreover, the intrinsically high photothermal conversion efficiency of Ti3C2-Cu-PEG further promotes the NDT process. In vitro and in vivo experiments, the Ti3C2-Cu-PEG nanosystem showed excellent antitumor effect in 4T1 tumor-bearing mice by amplifying oxidative stress under NIR-II stimulation. This work highlights an easily synergistic nanosystem with remodeling TME and combined photothermal therapy to enhance the therapeutic effect of NDT in tumor therapy.

Zhenzhang Lu,1,2,* Yuxiang Zhou,3,* Guohui Nie,1 Beiping Miao,1 Yongtian Lu,1 Tao Chen1 1Department of Otorhinolaryngology, The First Affiliated Hospital of Shenzhen University/Shenzhen Second People’s Hospital, Shenzhen, Guangdong Province, 518000, People’s Republic of China; 2Department of Otorhinolaryngology, South China Hospital of Shenzhen University, Shenzhen, Guangdong Province, 518000, People’s Republic of China; 3Department of Otorhinolaryngology, People’s Hospital of Shenzhen Baoan District, Shenzhen, Guangdong Province, 518000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tao Chen, Department of Otorhinolaryngology, The First Affiliated Hospital of Shenzhen University/Shenzhen Second People’s Hospital, No. 3002 Sungang West Road, Shenzhen, Guangdong Province, 518000, People’s Republic of China, Tel +86755-83366388, Email chentaozsu@126.comBackground: Accurate forecasting of the risk of death is crucial for people living with head and neck mucosal melanoma (HNMM). We aimed to establish and validate an effective prognostic nomogram for HNMM.Methods: Patients with HNMM who underwent surgery between 2010 and 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database for model construction. After eliminating invalid and missing clinical information, 288 patients were ultimately identified and randomly divided into a training cohort (199 cases) and a validation cohort (54 cases). Univariate and multivariate Cox proportional hazards regression analyses were performed in the training cohort to identify prognostic variables. Independent influencing factors were used to build the model. Through internal verification (training cohort) and external verification (validation cohort), the concordance indexes (C-indexes) and calibration curves were used to evaluate the predictive value of the nomogram.Results: For the training cohort, five independent risk predictors, namely age, location, T stage, N stage, and surgery, were selected, and nomograms with estimated 1- and 3-year overall survival (OS) and cancer-specific survival (CSS) were established. The C-index showed that the predictive performance of the nomogram was better than that of the TNM staging system and was internally verified (through the training queue: OS: 0.764 vs 0.683, CSS: 0.783 vs 0.705) and externally verified (through the verification queue: OS: 0.808 vs 0.644, CSS: 0.823 vs 0.648). The calibration curves also showed good agreement between the prediction based on the nomogram and the observed survival rate.Conclusion: The nomogram prediction model can more accurately predict the prognosis of HNMM patients than the traditional TNM staging system and may be beneficial for guiding clinical treatment.Keywords: head and neck mucosal melanoma, SEER, nomogram, overall survival, cancer-specific survival

Familial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole-genome sequencing in 15 Polish families of many affected individuals, without mutations in known CRC predisposing genes. We focused on loss-of-function variants and functionally characterized them. We identified a frameshift variant in the

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing on six members of a Polish family diagnosed with CRC and identified a novel germline variant in the protein tyrosine kinase 7 (inactive) gene (

Germline mutations in predisposition genes account for only 20% of all familial colorectal cancers (CRC) and the remaining genetic burden may be due to rare high- to moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer-predisposing variants, we performed whole exome sequencing on three CRC cases and three unaffected members of a Polish family and identified two novel heterozygous variants: a coding variant in APC downregulated 1 gene (APCDD1, p.R299H) and a non-coding variant in the 5' untranslated region (UTR) of histone deacetylase 5 gene (HDAC5). Sanger sequencing confirmed the variants segregating with the disease and Taqman assays revealed 8 additionalAPCDD1variants in a cohort of 1705 familial CRC patients and no furtherHDAC5variants. Proliferation assays indicated an insignificant proliferative impact for theAPCDD1variant. Luciferase reporter assays using theHDAC5variant resulted in an enhanced promoter activity. Targeting of transcription factor binding sites of SNAI-2 and TCF4 interrupted by theHDAC5variant showed a significant impact of TCF4 on promoter activity of mutatedHDAC5. Our findings contribute not only to the identification of unrecognized genetic causes of familial CRC but also underline the importance of 5'UTR variants affecting transcriptional regulation and the pathogenesis of complex disorders.

In 2018 alone, colorectal cancer (CRC) accounted for 10.2% among all cancer cases. It is known to be a consequence of accumulated alterations in the genome. Several studies on genetics have improved our understanding of CRC. While genetics play its role as the first code of genome, role of epigenetics in CRC as the second code of genome has been highlighted in the last decades. We focus on the essential factors like DNA methylation drivers-writer, reader, eraser and non-coding RNA, miRNA and long non-coding RNAs associated with CRC.

Colorectal cancer (CRC) is the third most known type of cancer in developing countries and is one of the leading causes of deaths around the world. The current treatment therapies for CRC are increasing nowadays since there are large variations seen among individuals in terms of diagnosis and response to drugs used to manage CRC owing to biomolecular heterogeneity. Around 15% of CRC cases are due to defect in the DNA mismatch repair (MMR) system, featured by microsatellite instability (MSI) characteristics. We highliht the role of DNA mismatch repair genes in CRC, its diagnosis and management including targeted therapies and immune checkpoint blockade therapies for controlling the individual CRC therapy response and treatment.

Colorectal cancer (CRC) shows one of the largest proportions of familial cases among different malignancies, but only 5–10% of all CRC cases are linked to mutations in established predisposition genes. Thus, familial CRC constitutes a promising target for the identification of novel, high- to moderate-penetrance germline variants underlying cancer susceptibility by next generation sequencing. In this study, we performed whole genome sequencing on three members of a family with CRC aggregation. Subsequent integrative in silico analysis using our in-house developed variant prioritization pipeline resulted in the identification of a novel germline missense variant in the SRC gene (V177M), a proto-oncogene highly upregulated in CRC. Functional validation experiments in HT-29 cells showed that introduction of SRCV177M resulted in increased cell proliferation and enhanced protein expression of phospho-SRC (Y419), a potential marker for SRC activity. Upregulation of paxillin, β-Catenin, and STAT3 mRNA levels, increased levels of phospho-ERK, CREB, and CCND1 proteins and downregulation of the tumor suppressor p53 further proposed the activation of several pathways due to the SRCV177M variant. The findings of our pedigree-based study contribute to the exploration of the genetic background of familial CRC and bring insights into the molecular basis of upregulated SRC activity and downstream pathways in colorectal carcinogenesis.

Familial inheritance in non-medullary thyroid cancer (NMTC) is an area that has yet to be adequately explored. Despite evidence suggesting strong familial clustering of non-syndromic NMTC, known variants still account for a very small percentage of the genetic burden. In a recent whole genome sequencing (WGS) study of five families with several NMTCs, we shortlisted promising variants with the help of our in-house developed Familial Cancer Variant Prioritization Pipeline (FCVPPv2). Here, we report potentially disease-causing variants in checkpoint kinase 2 (CHEK2), Ewing sarcoma breakpoint region 1 (EWSR1) and T-lymphoma invasion and metastasis-inducing protein 1 (TIAM1) in one family. Performing WGS on three cases, one probable case and one healthy individual in a family with familial NMTC left us with 112254 variants with a minor allele frequency of less than 0.1%, which was reduced by pedigree-based filtering to 6368. Application of the pipeline led to the prioritization of seven coding and nine non-coding variants from this family. The variant identified in CHEK2, a known tumor suppressor gene involved in DNA damage-induced DNA repair, cell cycle arrest, and apoptosis, has been previously identified as a germline variant in breast and prostate cancer and has been functionally validated by Roeb et al. in a yeast-based assay to have an intermediate effect on protein function. We thus hypothesized that this family may harbor additional disease-causing variants in other functionally related genes. We evaluated two further variants in EWSR1 and TIAM1 with promising in silico results and reported interaction in the DNA-damage repair pathway. Hence, we propose a polygenic mode of inheritance in this family. As familial NMTC is considered to be more aggressive than its sporadic counterpart, it is important to identify such susceptibility genes and their associated pathways. In this way, the advancement of personalized medicine in NMTC patients can be fostered. We also wish to reopen the discussion on monogenic vs polygenic inheritance in NMTC and instigate further development in this area of research.

Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the Protection of Telomeres 1 (POT1) gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carrying POT1 p.V29L showed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation in POT1 has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers.

Transferrin-functionalized chitosan-graft-poly(l-lysine) dendrons (CS-PLLD-Tf) were synthesized in this work and then used to deliver the MMP-9 shRNA plasmid to HNE-1 cells for gene therapy. The obtained CS-PLLD-Tf displayed excellent gene transfection in vitro, verifying the strategy of constructing a high-efficiency gene carrier by conjugating the multiple low generation PLLDs to one molecule of CS to form a copolymer. Particularly, CS-PLLD-Tf showed much higher gene transfection efficiency than PEI-25k and CS-PLLD in the presence of serum, and more than 40% HNE-1 cells were transfected. This result led to an obvious decrease in MMP-9 protein expression and the apoptosis of HNE-1 cells as well as inhibition of the growth and invasion of HNE-1 tumors. The in vivo anti-tumor assay showed that CS-PLLD-Tf delivered the MMP-9 plasmid effectively and the tumor volume decreased more than 77% compared with the PBS control group. Moreover, CS-PLLD-Tf displayed higher bioavailability and good biocompatibility such as lower cytotoxicity, excellent blood compatibility and non-toxicity to organs, suggesting a potential application in gene therapy of tumors.

Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole genome sequencing study of five families with recurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the Protection of Telomeres 1 (POT1) gene in one of the families. The results showed that the variant demonstrates a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293Tcells carrying POT1V29L showed increased telomere length in comparison to wild type cells, strongly suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. This study reports the first germline POT1 mutation in a family with a predominance of thyroid cancer, thereby expanding the spectrum of cancers associated with mutations in the shelterin complex.

Photoacoustic imaging (PAI) is an attractive imaging modality, which is promising for clinical cancer diagnosis due to its advantages on deep tissue penetration and fine spatial resolution. However, few tumor catalytic/responsive PAI strategies are developed. Here, we design an exosome-like nanozyme vesicle for in vivo H2O2-responsive PAI of nasopharyngeal carcinoma (NPC). The intrinsic peroxidase-like activity of graphene quantum dot nanozyme (GQDzyme) effectively converts the 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) into its oxidized form in the presence of H2O2. The oxidized ABTS exhibits strong near-infrared (NIR) absorbance, rendering it to be an ideal contrast agent for PAI. Thus, GQDzyme/ABTS nanoparticle is a novel type of catalytic PAI contrast agent, which is sensitive to H2O2 produced from NPC cells. Furthermore, we develop an approach to construct exosome-like nanozyme vesicle via biomimetic functionalization of GQDzyme/ABTS nanoparticle with natural erythrocyte membrane ...

Using Chlamydia trachomatis (Ct) as a complex model organism, we describe a method to generate bacterial whole-proteome microarrays using cell-free, on-chip protein expression. Expression constructs were generated by two successive PCRs directly from bacterial genomic DNA. Bacterial proteins expressed on microarrays display antigenic epitopes, thereby providing an efficient method for immunoprofiling of patients and allowing de novo identification of disease-related serum antibodies. Through comparison of antibody reactivity patterns, we newly identified antigens recognized by known Ct-seropositive samples, and antigens reacting only with samples from cervical cancer (CxCa) patients. Large-scale validation experiments using high-throughput suspension bead array serology confirmed their significance as markers for either general Ct infection or CxCa, supporting an association of Ct infection with CxCa. In conclusion, we introduce a method for generation of fast and efficient proteome immunoassays which can be easily adapted for other microorganisms in all areas of infection research.

Familial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole-genome sequencing in 15 Polish families of many affected individuals, without mutations in known CRC predisposing genes. We focused on loss-of-function variants and functionally characterized them. We identified a frameshift variant in the CYBA gene (c.246delC) in one family and a splice site variant in the TRPM4 gene (c.25–1 G > T) in another family. While both variants were absent or extremely rare in gene variant databases, we identified four additional Polish familial CRC cases and two healthy elderly individuals with the CYBA variant (odds ratio 2.46, 95% confidence interval 0.48–12.69). Both variants led to a premature stop codon and to a truncated protein. Functional characterization of the variants showed that knockdown of CYBA or TRPM4 depressed generation of reactive oxygen species (ROS) in LS174T and HT-29 cell lines. Knockdown of TRPM4 resulted in decreased MUC2 protein production. CYBA encodes a component in the NADPH oxidase system which generates ROS and controls, e.g., bacterial colonization in the gut. Germline CYBA variants are associated with early onset inflammatory bowel disease, supported with experimental evidence on loss of intestinal mucus barrier function due to ROS deficiency. TRPM4 encodes a calcium-activated ion channel, which, in a human colonic cancer cell line, controls calcium-mediated secretion of MUC2, a major component of intestinal mucus barrier. We suggest that the gene defects in CYBA and TRPM4 mechanistically involve intestinal barrier integrity through ROS and mucus biology, which converges in chronic bowel inflammation., L.Z. was supported by Zhejiang University Lu’s Graduate Education International Exchange Fund. E.A.V.’s lab was supported by grants from the Spanish Ministry of Science, Innovation and Universities, Plan Nacional de I+D+I 2013-2016, ISCIII (PI17/00227) co-funded by FEDER from Regional Development European Funds (European Union), and grant CSI242P18 (actuación cofinanciada P.O. FEDER 2014-2020 de Castilla y León) from the Consejería de Educación, Junta de Castilla y León. L.S.-M. was supported by a predoctoral fellowship from the Spanish Association Against Cancer (AECC), Junta Provincial de Valladolid (2019-2023). K.H. was supported by the EU Horizon 2020 program, grant No. 856620. A.K. is a recipient of the Ramalingaswami Re-Retry Faculty Fellowship (Grant; BT/RLF/Re-entry/38/2017). This article is based upon work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology).

Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of theProtection of Telomeres 1(POT1) gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carryingPOT1 p.V29Lshowed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation inPOT1has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers.

Binding of transcription factors to mutated DNA sequences is a likely regulator of cancer progression. Noncoding regulatory mutations such as those on the core promoter of the gene encoding human telomerase reverse transcriptase have been shown to affect gene expression in cancer. Using a protein microarray of 667 transcription factor DNA-binding domains and subsequent functional assays, we looked for transcription factors that preferentially bind the mutant hTERT promoter and characterized their downstream effects. One of them, friend leukemia integration 1 (FLI1), which belongs to the E26 transforming-specific family of transcription factors, exhibited particularly strong effects with respect to regulating hTERT expression, while the even better binding ELK3 did not. Depletion of FLI1 decreased expression of the genes for cyclin D1 (CCND1) and E2F transcription factor 2 (E2F2) resulting in a G1/S cell cycle arrest and in consequence a reduction of cell proliferation. FLI1 also affected CMTM7, another gene involved in G1/S transition, although by another process that suggests a balanced regulation of the tumor suppressor gene's activity via opposing regulation processes. FLI1 expression was found upregulated and correlated with an increase in CCND1 expression in pancreatic cancer and brain tumors. In non-neoplastic lung cells, however, FLI1 depletion led to rapid progression through the cell cycle. This coincides with the fact that FLI1 is downregulated in lung tumors. Taken together, our data indicate a cell cycle regulatory hub involving FLI1, hTERT, CCND1 and E2F2 in a tissue- and context-dependent manner.

Photoacoustic imaging (PAI) is an attractive imaging modality, which is promising for clinical cancer diagnosis due to its advantages on deep tissue penetration and fine spatial resolution. However, few tumor catalytic/responsive PAI strategies are developed. Here, we design an exosome-like nanozyme vesicle for in vivo H

Background Cysteinyl leukotriene (LT) has been proposed in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). This study sought to examine the expression of the LT receptor (LTR) in CRSwNP patients and evaluate the potential role of LTR antagonist (LTRA) in the management of eosinophilic CRSwNP (ECRS) patients. Methods Nasal polyps and uncinate process tissues were collected from 18 ECRS patients, 13 non-eosinophilic CRSwNP (non-ECRS) patients, and 16 control subjects. The messenger RNA (mRNA) and protein expression of LTR (cysteinyl leukotriene receptor 1 [CysLT1R] and cysteinyl leukotriene receptor 2 [CysLT2R]) was examined using quantitative reverse-transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, and Western blot analysis. Moreover, the effects of LTRA and steroids on total nasal symptom scores (TNSS) of uncontrolled ECRS patients were evaluated. Results The mRNA and protein expression of CysLT1R and CysLT2R was significantly increased in polyp tissues compared with healthy controls (p < 0.05). Compared with the non-ECRS subset, the ECRS subset showed significantly increased expression of CysLT1R and CysLT2R, as well as leukotriene C4 (LTC4) and leukotriene D4 (LTC4) levels (p < 0.05). Moreover, combined LTRA and steroids significantly decreased TNSS more than steroids alone in uncontrolled ECRS patients (p < 0.01). Conclusion Our findings indicate that LTR was differentially expressed between ECRS and non-ECRS patients, and that LTRA may be used as an additional therapy for ECRS patients.

Objective/Hypothesis Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by significant goblet hyperplasia and mucus hypersecretion. However, the molecular mechanism underlying mucin overexpression in CRSwNP has not been well characterized. This study sought to assess the expression of SAM-pointed domain-containing Ets-like factor (SPDEF) and its regulation of mucin production in CRSwNP patients. Study design Prospective laboratory-based study. Methods Polyp and control nasal tissues were collected from 27 CRSwNP patients and 15 control subjects. The expression of SPDEF and MUC5AC in the nasal tissues was examined by immunohistochemistry staining, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. In addition, SPDEF and MUC5AC expression was evaluated in cultured polyp epithelial cells and bronchial epithelial cells (BECs) in the presence of proinflammatory cytokines, corticosteroids and SPDEF small interfering RNA (siRNA) using qRT-PCR and western blot analysis. Results We found significantly increased SPDEF and MUC5AC expression in CRSwNP patients compared to the controls (P

Tuberculosis (TB) is an important infectious disease of humans and other animals. Conventional diagnostic methods, including the tuberculin skin test, chest X‑rays and bacterial culture, have certain innate disadvantages for the early, rapid and specific diagnosis of tuberculosis. The present study aimed to identify a novel diagnostic biomarker to overcome these disadvantages. The potential target identified in the present study was tissue inhibitor of metalloproteinases 1 (TIMP‑1), which has previously been demonstrated to be critical in the immune response to TB. The concentration of TIMP‑1 in the blood was determined using a commercial ELISA kit, and the relative mRNA expression levels following bacterial infection were detected by reverse transcription‑quantitative polymerase chain reaction. Based on a clinical and microbiological diagnosis, the ELISA for plasma TIMP‑1 had a sensitivity of 91.80% [95% confidence interval (CI): 85.44, 96.00] and a specificity of 91.41% (95% CI: 85.14, 95.63). In a THP‑1 cell model, Bacillus Calmette‑Guerin and Mycobacterium bovis significantly upregulated the mRNA expression levels of TIMP‑1 post infection in a time‑dependent manner (P=0.006 for BCG 24 h PI, P=3.2x10‑7 for M. bovis 24 PI). The results of the present study indicate that plasma TIMP‑1 may be a potential biomarker for the diagnosis of TB.

Objective: There are controversies on management of carotid artery invasion in advanced head and neck cancer. En bloc resection has been considered a curative modality. In this study, we evaluated the feasibility of using expanded polytetrafluoroethylene (ePTFE) in reconstructing the common carotid artery in patients with carotid artery invasion requiring resection. Method: A retrospective study including 13 patients managed from 2002 to 2005. All patients underwent en bloc resection of the tumor and internal carotid artery then reconstructed with ePTFE. Results: All patients had en bloc resection of the tumor together with internal carotid artery and reconstruction with ePTFE. Some patients required wound coverage with myocutaneous flaps in eight patients and local flaps in five patients. Intraoperative shunting was used in all patients. Intraoperative heparin infusion and postoperative low dose aspirin were used to prevent thrombosis. One patient developed graft blowout and he was treated with ligation without hemiplegia. One patient had minor stroke. The follow-up period was 18.4 ± 8.6 months. No patient suffered from neurological deficit or graft occlusion. Disease survival was 61.5% in 1 year and 38.5% in 2 years. Overall survival was 18.3 months. Conclusion: En bloc resection and tumor together with carotid artery and ePTFE reconstruction is shown to be a feasible modality in treatment of advanced head and neck cancer with carotid artery invasion.

Traditionally, immunology is mainly about the study of the immune response against foreign antigens, such as bacteria and viruses. Accordingly, tumor cells expressing alien or altered antigens make the attractive targets against which cancer immunology is initiated. However, recent comprehensive studies demonstrated that most prevalent antigens recognized by our immune system in cancer are those shared, nonmutated self-antigens expressed also by normal tissue cells. Thus, how to break the self-tolerance and avoid the concomitant autoimmunity remain the two challenges in cancer immunology. Dendritic cells (DCs) are the most effective antigen-presenting cells. They are capable of capturing, processing, and presenting antigens to T- and B-cells. This feature targets dendritic cells as the ideal candidates for breaking self-tolerance in cancer immunology. Clinical trials have demonstrated that dendritic cells are effective messengers. They circulate around the body and stimulate cytotoxic T-lymphocytes to clear tumor cells. Vaccination with DCs led to a clinical response in patients with melanoma, specifically those without significant autoimmunity. In this paper, we will examine the strategies and efficacies of DC-based vaccinations in the treatment of patients with melanoma.

Cysteinyl leukotriene (LT) has been proposed in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). This study sought to examine the expression of the LT receptor (LTR) in CRSwNP patients and evaluate the potential role of LTR antagonist (LTRA) in the management of eosinophilic CRSwNP (ECRS) patients.Nasal polyps and uncinate process tissues were collected from 18 ECRS patients, 13 non-eosinophilic CRSwNP (non-ECRS) patients, and 16 control subjects. The messenger RNA (mRNA) and protein expression of LTR (cysteinyl leukotriene receptor 1 [CysLT1R] and cysteinyl leukotriene receptor 2 [CysLT2R]) was examined using quantitative reverse-transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, and Western blot analysis. Moreover, the effects of LTRA and steroids on total nasal symptom scores (TNSS) of uncontrolled ECRS patients were evaluated.The mRNA and protein expression of CysLT1R and CysLT2R was significantly increased in polyp tissues compared with healthy controls (p0.05). Compared with the non-ECRS subset, the ECRS subset showed significantly increased expression of CysLT1R and CysLT2R, as well as leukotriene C4 (LTC4) and leukotriene D4 (LTC4) levels (p0.05). Moreover, combined LTRA and steroids significantly decreased TNSS more than steroids alone in uncontrolled ECRS patients (p0.01).Our findings indicate that LTR was differentially expressed between ECRS and non-ECRS patients, and that LTRA may be used as an additional therapy for ECRS patients.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by significant goblet hyperplasia and mucus hypersecretion. However, the molecular mechanism underlying mucin overexpression in CRSwNP has not been well characterized. This study sought to assess the expression of SAM-pointed domain-containing Ets-like factor (SPDEF) and its regulation of mucin production in CRSwNP patients.Prospective laboratory-based study.Polyp and control nasal tissues were collected from 27 CRSwNP patients and 15 control subjects. The expression of SPDEF and MUC5AC in the nasal tissues was examined by immunohistochemistry staining, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. In addition, SPDEF and MUC5AC expression was evaluated in cultured polyp epithelial cells and bronchial epithelial cells (BECs) in the presence of proinflammatory cytokines, corticosteroids and SPDEF small interfering RNA (siRNA) using qRT-PCR and western blot analysis.We found significantly increased SPDEF and MUC5AC expression in CRSwNP patients compared to the controls (P .05); the mRNA level of SPDEF was positively correlated with MUC5AC expression in CRS patients (P .05). There was a significant difference in SPDEF and MUC5AC expression in eosinophilic and noneosinophilic CRSwNP patients (P .05). Interleukin (IL)-13, IL-8, and IL-17A significantly increased SPDEF and MUC5AC expression in vitro (P .05). SPDEF siRNA significantly inhibited SPDEF and MUC5AC expression in BECs in response to IL-13, IL-8, and IL-17A (P .05).Our findings suggested that SPDEF may be regarded as a promising therapeutic target for modulating mucus hypersecretion in CRSwNP.

PURPOSE: Chronic rhinosinusitis (CRS) is characterized by the excessive production of mucus. However, the molecular mechanism underlying mucin overproduction in CRS with or without nasal polyps (CRSwNP and CRSsNP, respectively) is poorly understood. This study was conducted to assess the importance of the transcription factor FoxA2 in mucin production and to investigate the targeting of FoxA2 as a potential therapeutic strategy for mucus hypersecretion in CRS patients. METHODS: We enrolled 15 CRSwNP patients, 15 CRSsNP patients, and 10 normal controls in this study. The expression levels of FoxA2, MUC5AC, and MUC5B in inflamed and healthy nasal tissues were examined via immunohistochemistry and quantitative reverse transcription-polymerase chain reaction, and the levels of several proinflammatory cytokines in nasal secretions were measured via FlowCytomix analysis. In addition, the expression of MUC5AC and FoxA2 was determined in polyp-derived epithelial cells and NCI-H292 cells after in vitro stimulation. RESULTS: FoxA2 was significantly down-regulated, and MUC5AC and MUC5B were significantly up-regulated in both the CRSwNP and CRSsNP patients compared to the controls (P

About 15% of colorectal cancer (CRC) patients have first-degree relatives affected by the same malignancy. However, for most families the cause of familial aggregation of CRC is unknown. To identify novel high-to-moderate-penetrance germline variants underlying CRC susceptibility, we performed whole exome sequencing (WES) on four CRC cases and two unaffected members of a Polish family without any mutation in known CRC predisposition genes. After WES, we used our in-house developed Familial Cancer Variant Prioritization Pipeline and identified two novel variants in the solute carrier family 15 member 4 (SLC15A4) gene. The heterozygous missense variant, p. Y444C, was predicted to affect the phylogenetically conserved PTR2/POT domain and to have a deleterious effect on the function of the encoded peptide/histidine transporter. The other variant was located in the upstream region of the same gene (GRCh37.p13, 12_129308531_C_T; 43 bp upstream of transcription start site, ENST00000266771.5) and it was annotated to affect the promoter region of SLC15A4 as well as binding sites of 17 different transcription factors. Our findings of two distinct variants in the same gene may indicate a synergistic up-regulation of SLC15A4 as the underlying genetic cause and implicate this gene for the first time in genetic inheritance of familial CRC.