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Genetics and immune therapy

Catarina Roma-Rodrigues, Rita Mendes, Pedro V Baptista, Alexandra R Fernandes
Cancer development is highly associated to the physiological state of the tumor microenvironment (TME). Despite the existing heterogeneity of tumors from the same or from different anatomical locations, common features can be found in the TME maturation of epithelial-derived tumors. Genetic alterations in tumor cells result in hyperplasia, uncontrolled growth, resistance to apoptosis, and metabolic shift towards anaerobic glycolysis (Warburg effect). These events create hypoxia, oxidative stress and acidosis within the TME triggering an adjustment of the extracellular matrix (ECM), a response from neighbor stromal cells (e...
February 15, 2019: International Journal of Molecular Sciences
Jahnavi Aluri, Mukesh Desai, Maya Gupta, Aparna Dalvi, Antony Terance, Sergio D Rosenzweig, Jennifer L Stoddard, Julie E Niemela, Vasundhara Tamankar, Snehal Mhatre, Umair Bargir, Manasi Kulkarni, Nitin Shah, Amita Aggarwal, Harsha Prasada Lashkari, Vidya Krishna, Geeta Govindaraj, Manas Kalra, Manisha Madkaikar
Severe combined immunodeficiency (SCID) represents one of the most severe forms of primary immunodeficiency (PID) disorders characterized by impaired cellular and humoral immune responses. Here, we report the clinical, immunological, and molecular findings in 57 patients diagnosed with SCID from India. Majority of our patients (89%) presented within 6 months of age. The most common clinical manifestations observed were recurrent pneumonia (66%), failure to thrive (60%), chronic diarrhea (35%), gastrointestinal infection (21%), and oral candidiasis (21%)...
2019: Frontiers in Immunology
Lingfan Xu, Junyi Chen, Weipeng Liu, Chaozhao Liang, Hailiang Hu, Jiaoti Huang
Since androgen receptor (AR) signaling is critically required for the development of prostate cancer (PCa), targeting AR axis has been the standard treatment of choice for advanced and metastatic PCa. Unfortunately, although the tumor initially responds to the therapy, treatment resistance eventually develops and the disease will progress. It is therefore imperative to identify the mechanisms of therapeutic resistance and novel molecular targets that are independent of AR signaling. Recent advances in pathology, molecular biology, genetics and genomics research have revealed novel AR-independent pathways that contribute to PCa carcinogenesis and progression...
January 2019: Asian Journal of Urology
Gina Chia-Yi Chu, Leland W K Chung, Murali Gururajan, Chia-Ling Hsieh, Sajni Josson, Srinivas Nandana, Shian-Ying Sung, Ruoxiang Wang, Jason Boyang Wu, Haiyen E Zhau
This article describes cell signaling network of metastatic prostate cancer (PCa) to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics. The article focuses on our recent progress in the understanding of: 1) The plasticity and dynamics of tumor-stroma interaction; 2) The significance of epigenetic reprogramming in conferring cancer growth, invasion and metastasis; 3) New insights on altered junctional communication affecting PCa bone and brain metastases; 4) Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy; 5) Genetic-based therapy to co-target tumor and bone stroma; 6) PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis; 7) The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis; and 8) Characterization of imprinting cluster of microRNA, in tumor-stroma interaction...
January 2019: Asian Journal of Urology
Donald C Vinh
Fungal diseases are a threat to human health. Therapies targeting the fungus continue to lead to disappointing results. Strategies targeting the host response represent unexplored opportunities for innovative treatments. To do so rationally requires the identification and neat delineation of critical mechanistic pathways that underpin human antifungal immunity. The study of humans with single-gene defects of the immune system, i.e. inborn errors of immunity (IEIs), provides a foundation for these paragdims...
February 18, 2019: Expert Review of Clinical Immunology
Jong Woo Lee, Yu Zhang, Kyung Jin Eoh, Roshan Sharma, Miguel F Sanmamed, Jenny Wu, Justin Choi, Hee Sun Park, Akiko Iwasaki, Edward Kaftan, Lieping Chen, Vali Papadimitrakopoulou, Roy S Herbst, Ja Seok Koo
PURPOSE: To characterize the tumor-infiltrating immune cells population in Kras/p53-driven lung tumors and to evaluate the combinatorial anti-tumor effect with MEK inhibitor (MEKi), trametinib, and immunomodulatory monoclonal antibodies (mAbs) targeting either programmed cell death protein-1 (PD-1) or programmed cell death protein ligand 1 (PD-L1) in vivo. EXPERIMENTAL DESIGN: Trp53FloxFlox ;KrasG12D/+ ;Rosa26LSL-Luciferase/LSL-Luciferase (PKL) genetically engineered mice were utilized to develop autochthonous lung tumors with intratracheal delivery of adenoviral Cre recombinase...
February 13, 2019: Journal of Thoracic Oncology
Jasmine Kaur, Abdelkader Daoud, Scott T Eblen
BACKGROUND: Epigenetic alterations comprise key regulatory events that dynamically alter gene expression and their deregulation is commonly linked to the pathogenesis of various diseases, including cancer. Unlike DNA mutations, epigenetic alterations involve modifications to proteins and nucleic acids that regulate chromatin structure without affecting the underlying DNA sequence, altering the accessibility of the transcriptional machinery to the DNA, thus modulating gene expression. In cancer cells, this often involves the silencing of tumor suppressor genes or the increased expression of genes involved in oncogenesis...
February 14, 2019: Current Molecular Pharmacology
Marcel P Trefny, Sacha I Rothschild, Franziska Uhlenbrock, Dietmar Rieder, Benjamin Kasenda, Michal A Stanczak, Fiamma Berner, Abhishek S Kashyap, Monika Kaiser, Petra Herzig, Severin Poechtrager, Daniela S Thommen, Florian Geier, Spasenija Savic, Philip Jermann, Ilaria Alborelli, Stefan Schaub, Frank Stenner, Martin Früh, Zlatko Trajanoski, Lukas Flatz, Kirsten D Mertz, Alfred Zippelius, Heinz Läubli
PURPOSE: PD-(L)1 blocking antibodies have clinical activity in metastatic non-small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade.Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells were collected from 35 NSCLC patients receiving nivolumab monotherapy...
February 14, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Elizabeth A Blakeway, Noha Elshimy, Andrew Muinonen-Martin, Maria Marples, Bipin Mathew, Angana Mitra
Checkpoint blockade immunotherapy has revolutionized the treatment of advanced melanoma, with impressive survival benefits attained through upregulation of the anticancer immune response. Blockade of regulatory checkpoint molecules can, however, also result in aberrant immune activation leading to undesirable inflammation and autoimmunity. Although many genetic determinants have been described in patients with primary autoimmune diseases, it is uncertain whether patients developing autoimmune skin disease as an adverse effect of anti-PD-1 therapy share the same genetic risks...
February 11, 2019: Melanoma Research
Neelam Mukherjee, Karen M Wheeler, Robert S Svatek
PURPOSE OF REVIEW: Bacillus Calmette-Guérin (BCG) is the standard immune therapy for nonmuscle invasive bladder cancer. A systematic review of published articles regarding BCG treatment of bladder cancer was conducted and a commentary of these is provided to gain a perspective of the current major developments in the field. RECENT FINDINGS: Several BCG strains are utilized worldwide. As the understanding of genetic and phenotypic differences in these strains is elucidated, inquiries into the potential clinical effects of these various strains have been studied...
February 11, 2019: Current Opinion in Urology
Qiong-Zhen Zeng, Fan Yang, Chen-Guang Li, Li-Hui Xu, Xian-Hui He, Feng-Yi Mai, Chen-Ying Zeng, Cheng-Cheng Zhang, Qing-Bing Zha, Dong-Yun Ouyang
Microtubules play critical roles in regulating the activation of NLRP3 inflammasome and microtubule-destabilizing agents such as colchicine have been shown to suppress the activation of this inflammasome. However, it remains largely unknown whether paclitaxel, a microtubule-stabilizing agent being used in cancer therapy, has any influences on NLRP3 inflammasome activation. Here we showed that paclitaxel pre-treatment greatly enhanced ATP- or nigericin-induced NLRP3 inflammasome activation as indicated by increased release of cleaved caspase-1 and mature IL-1β, enhanced formation of ASC speck, and increased gasdermin D cleavage and pyroptosis...
2019: Frontiers in Immunology
Sunil Singhal, Jason Stadanlick, Michael J Annunziata, Abhishek S Rao, Pratik S Bhojnagarwala, Shaun O'Brien, Edmund K Moon, Edward Cantu, Gwenn Danet-Desnoyers, Hyun-Jeong Ra, Leslie Litzky, Tatiana Akimova, Ulf H Beier, Wayne W Hancock, Steven M Albelda, Evgeniy B Eruslanov
Data from mouse tumor models suggest that tumor-associated monocyte/macrophage lineage cells (MMLCs) dampen antitumor immune responses. However, given the fundamental differences between mice and humans in tumor evolution, genetic heterogeneity, and immunity, the function of MMLCs might be different in human tumors, especially during early stages of disease. Here, we studied MMLCs in early-stage human lung tumors and found that they consist of a mixture of classical tissue monocytes and tumor-associated macrophages (TAMs)...
February 13, 2019: Science Translational Medicine
Abhishek Sharma, Sandhanakrishnan Cattavarayane
Viral vectors enable efficient transfection of ectopic DNA into hard to transfect cells. Viral vectors are normally used to obtain permanent modification of target cells, and tissues expect for the cases where integrase-deficient viruses are used. Here we describe a method to stably transfect metanephric mesenchyme cells isolated from the murine embryonic kidney at day E11.5. Using this method, it is possible to transfect hard to transfect cells and successfully evade host tissue immune response. Due to these advantages, this method has become one of the most frequently used in generating stable cell line, manipulation of tissues, and gene therapy...
2019: Methods in Molecular Biology
Asmaa M Zahran, Khalid I Elsayh, Khaled Saad, Mostafa M Embaby, Mervat A M Youssef, Yasser F Abdel-Raheem, Shaban M Sror, Shereen M Galal, Helal F Hetta, Mohamed Diab Aboul-Khair, Mohamd A Alblihed, Amira Elhoufey
Sickle cell disease (SCD) is a genetically inherited hemolytic anemia increasingly appreciated as a chronic inflammatory condition and hypercoagulable state with high thrombotic risk. It is associated with disturbed immune phenotype and function and circulating microparticles (MPs) derived from multiple cell sources. This study was carried out to determine MPs profiles in patients with sickle cell anemia (either on hydroxyurea (HU) therapy or those with no disease-modifying therapy) and to compare these profiles with healthy children...
January 2019: Clinical and Applied Thrombosis/hemostasis
Jürgen Scheller, Erika Engelowski, Jens M Moll, Doreen M Floss
Cytokines control immune-related events and are critically involved in a plethora of physiological and pathophysiological processes including autoimmunity and cancer development. Accordingly, modulation of natural cytokine signaling by antibodies and small molecules has improved therapeutic regimens. Synthetic biology sets out to optimize immunotherapeutics, with chimeric antigen receptor (CAR) T cell immmunotherapy being the first example to combine synthetic biology with genetic engineering during therapy...
February 6, 2019: Trends in Immunology
Dalia Fleifel, Mai Atef Rahmoon, Abdelrahman AlOkda, Mostafa Nasr, Menattallah Elserafy, Sherif F El-Khamisy
Stem cells serve as potential therapeutics due to their high proliferative capacity, low immunogenic reactivity and their differentiating capabilities. Several pre-clinical and early-stage clinical studies are carried out to treat genetic diseases, cancers and neurodegenerative disorders with promising preliminary results. However, there are still many challenges that scientists are trying to overcome such as the unclear expression profile of stem cells in vivo, the homing of stem cells to the site of injury and their potential immune-reactivity...
December 2018: Journal, Genetic Engineering & Biotechnology
Valentina Martin, Cristina Chiriaco, Chiara Modica, Anna Acquadro, Marco Cortese, Francesco Galimi, Timothy Perera, Loretta Gammaitoni, Massimo Aglietta, Paolo M Comoglio, Elisa Vigna, Dario Sangiolo
BACKGROUND: Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immune-evasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-γ modulation of PD-L1/PD-L2 in MET-amplified tumours. METHODS: PD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-γ were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-γ stimulation, and after anti-MET therapy...
February 6, 2019: British Journal of Cancer
Carlos Pérez-Arques, María Isabel Navarro-Mendoza, Laura Murcia, Carlos Lax, Pablo Martínez-García, Joseph Heitman, Francisco E Nicolás, Victoriano Garre
Mucormycosis is an emerging fungal infection that is often lethal due to the ineffectiveness of current therapies. Here, we have studied the first stage of this infection-the germination of Mucor circinelloides spores inside phagocytic cells-from an integrated transcriptomic and functional perspective. A relevant fungal gene network is remodeled in response to phagocytosis, being enriched in crucial functions to survive and germinate inside the phagosome, such as nutritional adaptation and response to oxidative stress...
February 5, 2019: MBio
Nir Grabie, Andrew H Lichtman, Robert Padera
T lymphocyte-mediated immune responses in the heart are potentially dangerous because they can interfere with the electromechanical function. Furthermore, the myocardium has limited regenerative capacity to repair damage caused by effector T cells. Myocardial T cell responses are normally suppressed by multiple mechanisms of central and peripheral tolerance. T cell inhibitory molecules, so called immune checkpoints, limit the activation and effector function of heart-antigen reactive T cells that escape deletion during development in the thymus...
February 5, 2019: Cardiovascular Research
Hüseyin Sancar Bozkurt, Eamonn Mm Quigley, Banu Kara
Colorectal cancer is the third most common cancer and the third leading cause of cancer-related death. The pathogensesis of colorectal cancer involves a multi-step and multi-factorial process. Disruption of the gut microbiota has been associated with gastrointestinal diseases such as colorectal cancer. The genus Bifidobacterium is considered an important component of the commensal microbiota and plays important roles in several homeostatic functions: immune, neurohormonal, and metabolic. Bifidobacterium animalis subsp...
2019: SAGE Open Medicine
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