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Genetics and immune therapy

Zhiliang Wang, Zheng Wang, Chuanbao Zhang, Xing Liu, Guanzhang Li, Shuai Liu, Lihua Sun, Jingshan Liang, Huimin Hu, Yanwei Liu, Wei Zhang, Tao Jiang
Glioma is the most common malignant tumor that primarily originated from brain tissue. Immune checkpoints have been increasingly emphasized as targets for treating malignant tumors. B7-H3, has been identified as an immune checkpoint which shows potential values for targeting therapies. We set out to characterize the expression pattern and biological function of B7-H3 in brain gliomas via high-throughput data obtained from CGGA and TCGA projects. B7-H3 was upregulated in higher grade gliomas than that in lower grade gliomas in both CGGA and TCGA datasets...
July 20, 2018: Cancer Science
Sidhant Seth, Ann Ager, Mark Arends, Ian M Frayling
Recent work has provided evidence for genetic and molecular heterogeneity in colorectal cancers (CRCs) arising in patients with Lynch syndrome (LS), dividing these into two groups: G1 and G2. In terms of mutation and gene expression profile, G1 CRCs bear resemblance to sporadic CRCs with microsatellite instability (MSI), whereas G2 CRCs are more similar to microsatellite stable CRCs. Here we review the current state of knowledge on pathways of precursor progression to CRC in LS and how these might tie in with the new findings...
July 20, 2018: Journal of Pathology
Sam Chen, Josh Zaifman, Jayesh A Kulkarni, Igor V Zhigaltsev, Ying K Tam, Marco A Ciufolini, Yuen Yi C Tam, Pieter R Cullis
Lipid nanoparticles (LNPs) are playing a leading role in enabling clinical applications of gene therapies based on DNA or RNA polymers. One factor impeding clinical acceptance of LNP therapeutics is that LNP formulations of nucleic acid polymers can be immunostimulatory, necessitating co-administration of potent corticosteroid immunosuppressive agents. Here, we describe the development of hydrophobic prodrugs of a potent corticosteroid, dexamethasone, that can be readily incorporated into LNP systems. We show that the presence of the dexamethasone prodrug LD003 effectively suppresses production of cytokines such as KC-GRO, TNFα, IL-1β and IL-6 following intravenous administration of LNP loaded with immune stimulatory oligodeoxynucleotides containing cytosine-guanine dinucleotide motifs...
July 16, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Vishnu Hosur, Michelle L Farley, Benjamin E Low, Lisa M Burzenski, Leonard D Shultz, Michael V Wiles
Tylosis with esophageal cancer syndrome (TOC) is a rare autosomal dominant proliferative skin disease caused by missense mutations in the rhomboid 5 homolog 2 (RHBDF2) gene. TOC is characterized by thickening of the skin in the palms and feet and is strongly linked with the development of esophageal squamous cell carcinoma. Murine models of human diseases have been valuable tools for investigating the underlying genetic and molecular mechanisms of a broad range of diseases. Although current mouse models do not fully recapitulate all aspects of human TOC, and the molecular mechanisms underlying TOC are still emerging, the available mouse models exhibit several key aspects of the disease, including a proliferative skin phenotype, a rapid wound healing phenotype, susceptibility to epithelial cancer, and aberrant epidermal growth factor receptor (EGFR) signaling...
2018: Frontiers in Genetics
Thein Swe, Kevin B Kim
Malignant melanoma is generally chemo- and radio-resistant, and patients with advanced melanoma have a poor prognosis. However, with our increased understanding of the checkpoint immune molecules and genetic alterations of melanoma cells, more effective immunotherapy, such as anti CTLA4 antibody and anti PD-1 antibodies, and targeted drug therapy, such as BRAF inhibitors and MEK inhibitors, have been developed, resulting in improved overall survival and quality of life of patients with advanced melanoma. In addition, emerging technologies to develop prognostic and predictive biomarkers for response to systemic therapy could help clinicians make more accurate assessments of the disease and formulate more effective treatment plans...
July 17, 2018: Clinical & Experimental Metastasis
Qiyi Zhai, Fei Zhou, Mohamed M Ibrahim, Jingling Zhao, Xusheng Liu, Jun Wu, Lei Chen, Shaohai Qi
Skin grafting is the routine standard of care to manage third degree burns and problematic skin defects. Several commercially available dermal substitutes and biologic skin equivalents are placed in the wound bed to facilitate the healing process of the skin grafts, as well as to provide mechanical support for the cells to grow and to delay the contracture. To study pathology and develop new therapies, an immune-competent rat model is required. We have created two different skin graft animal models to mimic the clinical skin grafting operation, the dorsum skin grafting (DG) and inguinal skin grafting (IG)...
2018: American Journal of Translational Research
Alberto Puccini, Heinz-Josef Lenz, John L Marshall, David Arguello, Derek Raghavan, W Michael Korn, Benjamin A Weinberg, Kelsey Poorman, Arielle L Heeke, Philip A Philip, Anthony F Shields, Richard M Goldberg, Mohamed E Salem
BACKGROUND: The incidence of colorectal cancer (CRC) in younger patients is rising, mostly due to tumors in the descending colon and rectum. Therefore, we aimed to explore the molecular differences of left-sided CRC between younger (≤45 years) and older patients (≥65). SUBJECTS, MATERIALS, AND METHODS: In total, 1,126 CRC tumor samples from the splenic flexure to (and including) the rectum were examined by next-generation sequencing (NGS), immunohistochemistry, and in situ hybridization...
July 17, 2018: Oncologist
Ilgen Mender, Ryan LaRanger, Krishna Luitel, Michael Peyton, Luc Girard, Tsung-Po Lai, Kimberly Batten, Crystal Cornelius, Maithili P Dalvi, Michael Ramirez, Wenting Du, Lani F Wu, Steven J Altschuler, Rolf Brekken, Elisabeth D Martinez, John D Minna, Woodring E Wright, Jerry W Shay
Standard and targeted cancer therapies for late-stage cancer patients almost universally fail due to tumor heterogeneity/plasticity and intrinsic or acquired drug resistance. We used the telomerase substrate nucleoside precursor, 6-thio-2'-deoxyguanosine (6-thio-dG), to target telomerase-expressing non-small cell lung cancer cells resistant to EGFR-inhibitors and commonly used chemotherapy combinations. Colony formation assays, human xenografts as well as syngeneic and genetically engineered immune competent mouse models of lung cancer were used to test the effect of 6-thio-dG on targeted therapy- and chemotherapy-resistant lung cancer human cells and mouse models...
July 6, 2018: Neoplasia: An International Journal for Oncology Research
Sandra L Rodriguez-Zas, Cong Wu, Bruce R Southey, Jason C O'Connor, Scott E Nixon, Robmay Garcia, Cynthia Zavala, Marcus Lawson, Robert H McCusker, Elena V Romanova, Jonathan V Sweedler, Keith W Kelley, Robert Dantzer
BACKGROUND: Peripheral immune challenge can elicit microglia activation and depression-related symptoms. The balance of inflammatory signals in the tryptophan pathway can skew the activity of indoleamine-pyrrole 2,3 dioxygenase (IDO1) towards the metabolization of tryptophan into kynurenine (rather than serotonin), and towards neuroprotective or neurotoxic metabolites. The proteome changes that accompany inflammation-associated depression-related behaviors are incompletely understood...
June 30, 2018: Psychoneuroendocrinology
Ralf Weiskirchen, Sabine Weiskirchen, Frank Tacke
Hepatic fibrosis is characterized by the formation and deposition of excess fibrous connective tissue, leading to progressive architectural tissue remodeling. Irrespective of the underlying noxious trigger, tissue damage induces an inflammatory response involving the local vascular system and the immune system and a systemic mobilization of endocrine and neurological mediators, ultimately leading to the activation of matrix-producing cell populations. Genetic disorders, chronic viral infection, alcohol abuse, autoimmune attacks, metabolic disorders, cholestasis, alterations in bile acid composition or concentration, venous obstruction, and parasite infections are well-established factors that predispose one to hepatic fibrosis...
2018: F1000Research
Daniel F Costa, Vladimir P Torchilin
Gene therapy has emerged as an alternative in the treatment of cancer, particularly in cases of resistance to chemo and radiotherapy. Different approaches to deliver genetic material to tumor tissues have been proposed, including the use of small non-coding RNAs due to their multiple mechanisms of action. However, such promise has shown limits in in vivo application related to RNA's biological instability and stimulation of immunity, urging the development of systems able to overcome those barriers. In this review, we discuss the use of RNA interference in cancer therapy with special attention to the role of siRNA and miRNA and to the challenges of their delivery in vivo...
July 12, 2018: Biomedical Microdevices
Antonio Di Sabatino, Marco V Lenti, Gino R Corazza, Carmen Gianfrani
Autoimmune and allergic disorders are highly prevalent conditions in which an altered or abnormal immune response is mounted against self- or environmental antigens, respectively. Antigen-based immunotherapy is a therapeutic option aimed at restoring the specific immune tolerance toward pathogenic antigens while leaving the rest of the immune system unaffected. This strategy proved efficacy especially in allergic diseases, including asthma, allergic rhinitis, and food allergies, but still has shortcomings for the treatment of autoimmune diseases...
2018: Frontiers in Medicine
Alexandra Sherman, Moanaro Biswas, Roland W Herzog
PURPOSE OF REVIEW: Hemophilia is an X-linked blood coagulation genetic disorder, which can cause significant disability. Replacement therapy for coagulation factor VIII (hemophilia A) or factor IX (hemophilia B) may result in the development of high-affinity alloantibodies ('inhibitors') to the replacement therapy, thus making it ineffective. Therefore, there is interest in directing immunological responses towards tolerance to infused factors. RECENT FINDINGS: In this review, we will discuss latest advancements in the development of potentially less immunogenic replacement clotting factors, optimization of current tolerance induction protocols (ITI), preclinical and clinical data of pharmacological immune modulation, hepatic gene therapy, and the rapidly advancing field of cell therapies...
July 9, 2018: Current Opinion in Hematology
Niloofar Naderi, Fariba Ebrahimzadeh, Mohammad Jazebi, Ali Namvar, Mehrdad Hashemi, Azam Bolhassani
OBJECTIVES: Development of neutralizing antibodies against factor VIII is the major complication in hemophilia care which makes replacement therapies ineffective. The reports showed that inflammatory cytokines play an important role in inhibitor production. In the present study, the relationship between inhibitor development and the polymorphisms of two cytokine genes was studied in severe hemophiliac patients from Iran. METHODS: In this case-control study, three polymorphisms of immune regulatory genes [TGF-β (rs1982037) and IL-2 (rs2069762, rs4833248)] were analyzed in 100 Iranian hemophilia A patients divided into 55 inhibitor positive and 45 inhibitor negative patients using Tetra primer ARMS PCR, and DNA sequencing...
July 11, 2018: Hematology (Amsterdam, Netherlands)
Xiaobo Wang, Shaoyi Fan, Hehai Pan, Wenli Chen, Hua Wang
Cancer is a complex and refractory disease, which can disseminate from primary site to a different site even at an early stage. Cancer immunotherapy harnesses host immune system to battle against cancer, but only a minority of patients benefit from it. Genetic-based technologies have significantly promoted the development of cancer immunotherapy. Here we describe genetic-based cancer immunotherapies in three aspects: recombinant cancer vaccine, immune checkpoint blockade therapy and adoptive cell transfer. In the future, multi-disciplinary collaboration will greatly increase the scope and effectiveness of cancer immunotherpy...
July 9, 2018: Briefings in Functional Genomics
Alicja Derkacz, Pawel Olczyk, Katarzyna Komosinska-Vassev
The nonspecific inflammatory bowel diseases (IBD) represent a heterogeneous group of chronic inflammatory disorders of the gastrointestinal tract, and Leśniowski-Crohn's disease (CD) and ulcerative colitis (UC) are among the two major clinical forms. Despite the great progress in understanding the pathogenesis of these diseases, their etiology remains unclear. Genetic, immune, and environmental factors are thought to play a key role. The correct diagnosis of nonspecific inflammatory bowel diseases as well as the determination of disease activity, risk stratification, and prediction of response to therapy still relies on a multidisciplinary approach based on clinical, laboratory, endoscopic, and histologic examination...
2018: Disease Markers
Marike L Broekman, Sybren L N Maas, Erik R Abels, Thorsten R Mempel, Anna M Krichevsky, Xandra O Breakefield
Glioblastomas are heterogeneous and invariably lethal tumours. They are characterized by genetic and epigenetic variations among tumour cells, which makes the development of therapies that eradicate all tumour cells challenging and currently impossible. An important component of glioblastoma growth is communication with and manipulation of other cells in the brain environs, which supports tumour progression and resistance to therapy. Glioblastoma cells recruit innate immune cells and change their phenotype to support tumour growth...
July 9, 2018: Nature Reviews. Neurology
Ananda Kumar Konreddy, Grandhe Usha Rani, Kyeong Lee, Yongseok Choi
Drug repurposing is a safe and successful pathway to speed up the novel drug discovery and development processes compared with de novo drug discovery approaches. Drug repurposing uses FDA-approved drugs and drugs that failed in clinical trials, which have detailed information of potential toxicity, formulation, and pharmacology. Technical advancements in the informatics, genomics, and biological sciences account for the major success of drug repurposing in identifying secondary indications of existing drugs...
July 5, 2018: Current Medicinal Chemistry
Jose Maria Bastida, Maria Luisa Giros, Rocio Benito, Kamila Janusz, Jesus Maria Hernandez-Rivas, Jose Ramon Gonzalez-Porras
Sitosterolemia is a recessive inherited metabolic disorder of unknown prevalence, characterized by increased levels of plasma plant sterols. It is caused by 28 and 31 variants in ABCG5 and ABCG8 genes, respectively, and is characterized by a predisposition to hyperabsorption and accumulation of toxic levels of plant sterols in plasma. Its clinical picture is extremely heterogeneous. The main clinical features are tendinous and cutaneous xanthomas, arthritis or arthralgia, premature cardiovascular disease and atherosclerosis...
July 5, 2018: Current Medicinal Chemistry
Nekane Terrades-Garcia, Maria C Cid
GCA is a chronic granulomatous vasculitis that affects large- and medium-sized vessels. Both the innate and the adaptive immune system are thought to play an important role in the initial events of the pathogenesis of GCA. Amplification cascades are involved in the subsequent development and progression of the disease, resulting in vascular inflammation, remodelling and occlusion. The development of large-vessel vasculitis in genetically modified mice has provided some evidence regarding potential mechanisms that lead to vascular inflammation...
February 1, 2018: Rheumatology
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