Discovery Category Highlights

Immune Checkpoint Blockade as a Novel Immunotherapeutic Strategy for Renal Cell Carcinoma: A Review of Clinical Trials

Abstract: Renal cell carcinoma (RCC) is a common genitourinary malignancy; when metastatic, it is almost uniformly fatal. For many years non-specific immunotherapy was the mainstay of treatment for metastatic RCC, but led to only modest success and significant side-effects. More recently, seven targeted therapy drugs have been approved to treat metastatic RCC; these drugs impede RCC cell growth, proliferation, and angiogenesis and have had a significant impact on patient outcomes, but with infrequent long term responders. Thus, a renewed emphasis on immunotherapy has emerged over the last several years with the development and testing of a novel class of immunotherapeutic agents called checkpoint inhibitors. These drugs have targeted the programmed cell death 1 (PD-1) and cytotoxic leukocyte antigen 4 (CTLA-4) pathways on regulatory T cells, leading to immune response enhancement and immune-mediated anti-tumor effects in multiple malignancies, including RCC. A number of studies recently reported utilizing checkpoint inhibitors, either alone or in combination with other checkpoint inhibitors or vascular endothelial growth factor targeting agents, and these studies have shown significant and at times durable responses in RCC patients. This has led to the development of further phase I, II, and III trials and this review will discuss the history and currently available data for immune checkpoint blockade in RCC. ... Read more

Targeted Therapy for Hereditary Cancer Syndromes: Neurofibromatosis Type 1, Neurofibromatosis Type 2, and Gorlin Syndrome

Abstract: Hereditary cancer syndromes are well known in the oncology community, typically affecting children, adolescents, and young adults and thereby resulting in great cumulative morbidity and mortality. These syndromes often lag behind their de novo counterparts in the development of approved novel treatment options due to their rarity in the general population. Recent work has allowed the identification of molecular aberrations and associated targeted therapies that may effectively treat these conditions. In this review, we seek to characterize some of the involved aberrations and associated targeted therapies for several germline malignancies, including Neurofibromatosis types 1 and 2, and Gorlin syndrome. Though patients with hereditary cancer syndromes may be too rare to effectively include in large clinical trials, by understanding the pathophysiology of these diseases, clinicians can attain insights into the use of targeted therapies in their own practice when treating affected individuals. ... Read more

Targeted Therapy for Hereditary Cancer Syndromes: Hereditary Breast and Ovarian Cancer Syndrome, Lynch Syndrome, Familial Adenomatous Polyposis, and Li-Fraumeni Syndrome

Abstract: Cancer genetics has rapidly evolved in the last two decades. Understanding and exploring the several genetic pathways in the cancer cell is the foundation of targeted therapy. Several genomic aberrations have been identified and their role in carcinogenesis is being explored. In contrast to most cancers where these mutations are acquired, patients with hereditary cancer syndromes have inherited genomic aberrations. The understanding of the molecular pathobiology in hereditary cancer syndromes has advanced dramatically. In addition, many molecularly targeted therapies have been developed that could have potential roles in the treatment of patients with hereditary cancer syndromes. In this review, we outline the presentation, molecular biology, and possible targeted therapies for two of the most widely recognized hereditary cancer syndromes -- hereditary breast and ovarian cancer syndrome and hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome). We will also discuss other syndromes such as familial adenomatous polyposis and Li-Fraumeni syndrome (TP53). ... Read more

The Contribution of Non-human Primate Models to the Development of Human Vaccines

Abstract: The non-human primates (NHPs) model in biomedical research has contributed to the study of human infectious, autoimmune, oncogenic, and neurological diseases. This review focuses on the importance of NHP models in vaccine development for tuberculosis, pertussis, Dengue, group A streptococcus (Streptococcus pyogenes) infection, HIV infection, and certain diseases in the elderly (influenza, for example). From understanding disease pathogenesis and mechanisms of protection, to assessing vaccine safety and efficacy, we discuss selected cases where the importance of the use of NHP models is highlighted. ... Read more

Exome Sequencing on Malignant Meningiomas Identified Mutations in Neurofibromatosis Type 2 (NF2) and Meningioma 1 (MN1) Genes

Abstract: Background: Meningiomas are tumors originating from the membranous layers surrounding the central nervous system, and are generally regarded as "benign" tumors of the brain. Malignant meningiomas are rare and are typically associated with a higher risk of local tumor recurrence and a poorer prognosis (median survival time <2 years). Previous genome-wide association studies and exome sequencing studies have identified genes that play a role in susceptibility to meningiomas, but these studies did not focus specifically on malignant tumors. Methods: We performed exome sequencing on five malignant meningiomas on the Illumina HiSeq2000 platform using Agilent SureSelect Human All Exon kits. We used wANNOVAR web server to annotate and prioritize variants, identified candidate genes with recurrent mutations, and validated selected mutations by Sanger sequencing. We next designed custom NimbleGen targeted region arrays on five candidate genes, and sequenced four additional malignant meningiomas. Results: From exome sequencing data, we identified several frequently mutated genes including NF2, MN1, ARID1B, SEMA4D, and MUC2, with private mutations in tumors. We sequenced these genes in four additional samples and identified potential driver mutations in NF2 (neurofibromatosis type 2) and MN1 (meningioma 1). Conclusions: We confirmed that mutations in NF2 may play a role in progression of meningiomas, and nominated MN1 as a candidate gene for malignant transformation of meningiomas. Our sample size is limited by the extreme rarity of malignant meningiomas, but our study represents one of the first sequencing studies focusing on the malignant subtype. ... Read more

Involvement of Pituitary Tumor Transforming Gene 1 in Psoriasis, Seborrheic Keratosis, and Skin Tumors

Abstract: Accumulating evidence suggests that pituitary tumor transforming gene 1 (PTTG1) is a potential biomarker for cancer malignancy and a cell-cycle regulatory protein. This investigation was performed to address the subcellular localization of PTTG1 and its possible involvement in proliferative skin diseases. In vitro primary-cultured keratinocytes and skin samples from psoriasis, seborrheic keratosis (SK), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) were investigated by immunofluorescence and real-time PCR. In normal skin, PTTG1 is localized predominantly in 10% of basal keratinocytes, while 30-40% in basal and suprabasal psoriatic keratinocytes. PTTG1 mRNA in psoriatic epidermis is about 5-fold more than that in normal one (P<0.01). PTTG1 is localized in cytoplasm in primary-cultured normal and psoriatic keratinocytes, and PTTG1 in HaCaT cells is distributed throughout the cytoplasm of metaphase cells. PTTG1 is seen at both G2 and M phases, and highest PTTG1 expression correlates with highest cyclin B1 expression and highest degree of nuclear pleomorphism at M phase. The positive rate of PTTG1 in SK, BCC, and SCC is about 10%, 20%, and more than 80%, respectively. PTTG1 siRNA, which knocks down the expression of PTTG1, reduced the invasive capacity of A431 cells. In conclusion, PTTG1 is a marker for proliferative skin diseases associated with cell cycle regulation and may aid in detection of aggressive cancers. ... Read more

Enterovirus Persistence as a Mechanism in the Pathogenesis of Type 1 Diabetes

Abstract: Beyond acute clinical conditions, the role of enteroviruses (EVs) in chronic human diseases has been described. Although they are considered as highly cytolytic viruses, EVs can persist in various tissues. The persistence is believed to play a major role in the pathogenesis of EV related chronic diseases such as type 1 diabetes (T1D). T1D is characterized by an autoimmune destruction of pancreatic beta cells, and results from interplay between a genetic predisposition, the immune system, and environmental factors. EVs and especially group B coxsackieviruses (CVB) have been the most incriminated as exogenous agents involved in the development of T1D. Enteroviral persistence is the result of a virus-host coevolution combining a cell resistance to lysis through mutations or down-regulation of viral receptor, and a decrease of the viral replication by genomic modifications or the production of a stable double-stranded RNA form. CVB can persist in pancreatic cells and therefore could trigger, in genetically predisposed individuals, the autoimmune destruction of beta cells mainly through an activation of inflammation. The persistence of the virus in other tissues such as intestine, blood cells, and thymus has been described, and could also contribute to some extent to the enteroviral pathogenesis of T1D. The molecular and cellular mechanisms of CVB persistence and the link with the development of T1D should be investigated further. ... Read more

Challenges to Chimeric Antigen Receptor (CAR)-T Cell Therapy for Cancer

Abstract: Chimeric antigen receptor (CAR)-expressing T cells have demonstrated potent clinical efficacy in patients with B cell malignancies. However, the use of CAR-T cell therapy targeting other cancers has, in part, been limited by both the induction of antigen-specific toxicities targeting normal tissues expressing the target-antigen, and the extreme potency of CAR-T cell treatments resulting in life-threatening cytokine-release syndromes. Herein, we discuss toxicities associated with CAR-T cell therapy in the clinic. Further, we discuss potential clinical interventions to ameliorate these toxicities and the application of preclinical animal models to predict the clinical utility of CAR-T cell therapy. ... Read more

Mechanisms of Autoimmune Liver Disease

Abstract: The immune system of the liver is characterized by a predominant innate component. Several innate immune cell populations have been implicated in the pathogenesis of immune-mediated hepatic diseases, which are frequently associated with systemic symptoms or with co-morbidities affecting other organ systems. Thus, next to tissue-specific factors, general tolerance mechanisms are affected in devastating hepatic disorders like primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), or primary biliary cirrhosis (PBC). The innate immune cell populations abundantly detected within the liver and endowed with potent immunomodulatory capacities include innate lymphoid cells (ILCs) and natural killer T (NKT) cells. While both ILCs and NKT cells can be activated by different cytokines and/or chemokines, NKT cells also respond to (glyco-) lipid antigens engaging their canonical, semi-invariant TCR. Once activated, ILCs and NKT cells release copious amounts of Th1, Th2, and/or Th17 cytokines that shape subsequent innate and adaptive immune responses. Those immunomodulatory features as well as the recently described antigen-presenting capacity of ILCs and/or the bi-directional functional role of NKT cells might not only underlie the pathogenic mechanisms in the respective disorders, but also provide promising targets for clinical intervention. We will discuss these novel aspects as well as the role of alarmin-like cytokines such as IL-33 in the context of ILC and NKT cell activation and the consequences for the induction and progress of hepatic tissue damage and fibrosis. ... Read more

New Drugs for the Treatment of Hyperkalemia in Patients Treated with Renin-Angiotensin-Aldosterone System Inhibitors -- Hype or Hope?

Abstract: Hyperkalemia (serum potassium >5.5 mmol/L) may result from increased potassium intake, impaired distribution between the intracellular and extracellular spaces, and/or reduced renal excretion. Renin-angiotensin-aldosterone system inhibitors (RAASIs) represent an important therapeutic strategy in patients with hypertension, heart failure, chronic kidney disease, and diabetes, but hyperkalemia is a key limitation to fully titrate RAASIs in these patients who are most likely to benefit from treatment. Thus, we need new drugs to control hyperkalemia in these patients while maintaining the use of RAASIs. We review two new polymer-based, non-systemic agents under clinical development, patiromer calcium and zirconium silicate, designed to increase potassium loss via the gastrointestinal tract for the management of hyperkalemia. ... Read more

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