Understanding Of Molecular Targets Research Articles

Guardians Turned Culprits: NETosis and Its Influence on Pulmonary Fibrosis Development.

Idiopathic pulmonary fibrosis (IPF) is a debilitating, life-threatening irreversible lung disease characterized by the excessive accumulation of fibrotic tissue in the lungs, impairing their function. The exact mechanisms underlying Pulmonary fibrosis (PF) are multifaceted and not yet fully understood. Reports show that during COVID-19 pandemic, PF was dramatically increased due to the hyperactivation of the immune system. Neutrophils and macrophages are the patrolling immune cells that keep the microenvironment balanced. Neutrophil extracellular traps (NETs) are a normal protective mechanism of neutrophils. The chief components of the NETs include DNA, citrullinated histones, and anti-microbial peptides which are released by the activated neutrophils. However, it is becoming increasingly evident that hyperactivation of immune cells can also turn into criminals when it comes to pathological state. Dysregulated NETosis may contribute to sustained inflammation, overactivation of fibroblasts, and ultimately promoting collagen deposition which is the characteristic feature of PF. The role of NETs along with inflammation is attaining greater attention. However, seldom researches are related to the relationship between NETs causing PF. This review highlights the cellular mechanism of NETs-induced pulmonary fibrosis, which could give a better understanding of molecular targets which may be helpful for treating NETs-induced PF.

Potential Effects of Geraniol on Cancer and Inflammation-Related Diseases: A Review of the Recent Research Findings.

Geraniol (GNL), a natural monoterpene, is found in many essential oils of fruits, vegetables, and herbs, including lavender, citronella, lemongrass, and other medicinal and aromatic plants. GNL is commonly used by the cosmetic and food industries and has shown a wide spectrum of pharmacological activities including anti-inflammatory, anticancer, antimicrobial, antioxidant, and neuroprotective activities. It represents a potential anti-inflammatory agent and a promising cancer chemopreventive agent, as it has been found to be effective against a broad range of cancers, including colon, prostate, breast, lung, skin, kidney, liver, and pancreatic cancer. Moreover, GNL scavenges free radicals and preserves the activity of antioxidant enzymes. In addition, GNL induces apoptosis and cell cycle arrest, modulates multiple molecular targets, including p53 and STAT3, activates caspases, and modulates inflammation via transcriptional regulation. In the present study, different modes of action are described for GNL's activity against cancer and inflammatory diseases. This compound protects various antioxidant enzymes, such as catalase, glutathione-S-transferase, and glutathione peroxidase. Experiments using allergic encephalomyelitis, diabetes, asthma, and carcinogenesis models showed that GNL treatment had beneficial effects with low toxicity. GNL has been shown to be effective in animal models and tumor cell lines, but there have not been any clinical studies carried out for it. The aim of the present review is to provide updated data on the potential effects of GNL on cancer and inflammation, and to enhance our understanding of molecular targets, involved pathways, and the possible use of GNL for clinical studies and therapeutic purposes in the treatment of cancer and inflammation-related diseases.

Non-prophylactic resveratrol-mediated protection of neurite integrity under chronic hypoxia is associated with reduction of Cav1.2 channel expression and calcium overloading.

Cellular hypoxia is a major cause of oxidative stress, culminating in neuronal damage in neurodegenerative diseases. Numerous ex vivo studies have implicated that hypoxia episodes leading to disruption of Ca2+ homeostasis and redox status contribute to the progression of various neuropathologies and cell death. Isolation and maintenance of primary cell culture being cost-intensive, the details of the time course relationship between Ca2+ overload, L-type Ca2+ channel function, and neurite retraction under chronic and long-term hypoxia remain undefined. In order to explore the effect of oxidative stress and Ca2+ overload on neurite length, first, we developed a 5-day-long neurite outgrowth model using N2a cell line. Second, we propose a chronic hypoxia model to investigate the modulation of the L-type Ca2+ channel (Cav1.2) and oxidative resistance gene (OXR1) expression level during the process of neurite retraction and neuronal damage over 32h. Thirdly, we developed a framework for quantitative analysis of cytosolic Ca2+, superoxide formation, neurite length, and constriction formation in individual cells using live imaging that provides an understanding of molecular targets. Our findings suggest that an increase in cytosolic Ca2+ is a feature of an early phase of hypoxic stress. Further, we demonstrate that augmentation in the L-type channel leads to amplification in Ca2+ overload, ROS accumulation, and a reduction in neurite length during the late phase of hypoxic stress. Next, we demonstrated that non-prophylactic treatment of resveratrol leads to the reduction of calcium overloading under chronic hypoxia via lowering of L-type channel expression. Finally, we demonstrate that resveratrol-mediated reduction of Cav1.2 channel and STAT3 expression are associated with retention of neurite integrity. The proposed in vitro model assumes significance in the context of drug designing and testing that demands monitoring of neurite length and constriction formations by imaging before animal testing.

Emerging antibody therapies for pancreatic adenocarcinoma: a review of recent phase 2 trials

ABSTRACT Introduction: Pancreatic adenocarcinoma is now the third-leading cause of cancer-related deaths in the US which can be attributed to rising incidence, diagnosis at advanced stages and early development of metastasis. Systemic therapy remains palliative with early development of resistance possibly related to the constitutive activation of ‘undruggable’ KRAS, immunosuppressive microenvironment, and intense desmoplasia. The advancements in molecular biology has led to the development and investigation of targeted and immune therapeutics. Areas covered: This study provides a comprehensive review of the literature to further the understanding of molecular targets with their respective antibody-based therapies in clinical development in pancreatic cancer. PubMed was systematically searched for English-language articles discussing antibody-based therapies under phase 2 clinical trial investigation in pancreatic adenocarcinoma. Expert opinion: PDAC remains highly resistant to chemotherapy with no significant improvement in survival for patients with advanced or metastatic cancer. Unfortunately, the majority of the antibody-based targeted and immune therapeutics have failed to meet their primary efficacy endpoints in early phase trials. However, there are a few promising antibody-based drugs with intriguing preliminary data that merit further investigation, while many more continue to be developed and investigated preclinically, and in early phase trials.

Abstract 1697: Molecular features of refractory metastatic breast cancer

Abstract Background: Breast cancer is the most frequently diagnosed cancer in women worldwide and metastatic disease remains generally incurable, indicating a need for new drug discovery for metastatic breast cancer. In this study, we investigated the molecular features of refractory metastatic breast cancer. Methods: 74 metastatic refractory breast cancer patients who received molecular screening using next generation sequencing (NGS) between 2015 and 2017 were included in this analysis. Clinical and pathologic characteristics of these patients were reviewed. Results: Among the 74 patients, 27%, 51.4%, 10.8%, 10.8% had hormone receptor (HR)-negative HER2-negative, HR-positive HER2-negative, HR-positive HER2-positive, HR-negative HER2 positive. 54.1%, 48.6%, 9.5%, 47.3% had liver, lung, brain, bone metastasis. The most significantly mutated genes in refractory HR-positive breast tumors included TP53 (54.3%), PIK3CA (52.2%), CCND1 (19.6%) and ESR1 (15.2%). The most significantly mutated genes in refractory HR-negative breast tumors included TP53 (82.1%), PIK3CA (50%), MYC (14.3%), NF1 (14.3%) and KRAS (10.7%). Genes in PI3K/AKT/mTOR pathway were significantly mutated in 76.1% of HR-positive and 82.1% of HR-negative refractory breast tumors, respectively. Mutation of genes involved in DNA damage response pathway were observed in 23.9% of HR-positive tumors and 32.1% of HR-negative tumors. 21.7% of HR-positive tumors and only 3.6% of HR-negative tumors harbored at least one gene alteration in FGFR pathway (P = 0.04). 30.4% (17/74) of HR-positive tumors and 10.7% (3/28) of HR-negative tumors carried at least one gene alteration in CDK pathway (P = 0.50). 63.6% of tumors with alterations in FGFR pathway concurrently harbored alterations in CDK pathway. Alterations in FGFR or CDK pathway were significantly correlated with liver metastasis (P = 0.001). In addition, TP53 mutation was significantly correlated with brain metastasis (P = 0.022). Conclusions: These results provide a better understanding of molecular targets in refractory metastatic breast cancer which may lead to an improvement in the development of novel therapeutic strategies. Citation Format: Zhanhong Chen, Yuzi Zhang, Jing Zhao, Shangli Cai, Yongmei Yin. Molecular features of refractory metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1697.

Advancing Treatment of Pituitary Adenomas through Targeted Molecular Therapies: The Acromegaly and Cushing Disease Paradigms

The current treatment of pituitary adenomas requires a balance of conservative management, surgical resection, and in select tumor types, molecular therapy. Acromegaly treatment is an evolving field where our understanding of molecular targets and drug therapies has improved treatment options for patients with excess growth hormone levels. We highlight the use of molecular therapies in this disease process and advances in this field, which may represent a paradigm shift for the future of pituitary adenoma treatment.

Alcohol Modulation of Extra-synaptic Gamma-aminobutyric Acid Type A Receptors

Development of effective treatment agents for the alcohol use disorders requires the detailed understanding of molecular targets of alcohol in the brain. The gamma-aminobutyric acid type A receptors (GABAARs) are the major molecular targets of alcohol in the central nervous system. Mediating inhibitory neurotransmission upon GABA binding in the vertebrate central nervous system, GABAARs are heteropentameric chloride channels, assembled from a large subunit pool encoded by 19 distinct genes. It is the subunit composition that determines the receptor’s biophysical properties, neurotransmitter affinity, the pharmacology, and the position on the cell i.e., synaptic or extra-synaptic. This review paper briefly presents the alcohol modulation of a specific GABAAR subtype located at the extra-synaptic sites with a subunit composition of alpha, beta and delta

Molecular-Targeted Therapies for Hematologic Malignancies

Major advances in the disciplines of hematology, genetics, biochemistry, and chemistry over the past decades have empowered investigators with the background and methods required for development of customized molecular-targeted therapies. The ability to identify signaling pathways that are dysregulated, to determine the associated mutations, and to develop chemical drugs toward a desired correction is now a realistic work flow. The landmark demonstration that BCR-ABL could be molecularly targeted and could have a major impact upon disease progression really ignited the field of targeted therapies for hematologic malignancies. Through much hard work, we now know the key drivers of some hematologic malignancies, and depending on the particular disease, we have an arsenal of agents available to act at multiple nodal points. Some enabling technologies that have been a key for these advances include small molecule screening, high throughput whole genome sequencing, mouse models for cancer, and gene and microRNA expression array analyses. In this special issue, we present a collection of seven articles that contribute to our understanding of molecular targets and the development of approaches for their inhibition or rationale use of existing agents or their derivatives. These targets range from very early initiators of malignancy to molecules that are already advanced into clinical studies. The first paper in this issue by A. Fathi and T. Abdel-Wahab “Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy” addresses the series of mutations identified that alter DNA and/or histone lysine methylation. These early epigenetic changes predispose to leukemogenesis and are relevant in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. The second paper by J. Okabe-Kado et al. “Extracellular NM23 protein as a therapeutic target for hematologic malignancies” describes extracellular NM23-H1 protein and its relationship with altered signaling pathways and growth/survival in AML. The third paper by S. Verma et al. “Gab adapter proteins as therapeutic targets for hematologic disease” describes the Grb2-associated adapter proteins (Gabs) as potential therapeutic targets playing major roles in regulation of multiple signaling pathways. These first three papers describe potential new targets that require further validation and greater specificity, but could have significant impact on the initiation and progression of hematologic malignancy. The fourth paper by X. Liu et al. “Molecular targets for the treatment of juvenile myelomonocytic leukemia” describes the outstanding progress made in identifying the mutations associated with activation of the Ras pathway in juvenile myelomonocytic leukemia (JMML), several of which are already targets of drugs that are being tested such as Ras and SHP-2. This paper additionally points toward protein:protein interactions as potential therapeutic targets such as SHP-2/Gab2 in hematopoiesis. The fifth paper by P. Argyriou et al. “The role of mTOR inhibitors for the treatment of B-cell lymphomas” focuses on the downstream activation of the mTOR pathway and the development and testing of new rapalogues and ATP-competitive inhibitors for clinical use. The mTOR pathway is central to cell survival and metabolism and represents a common target for many types of cancers. The sixth paper by F. Tzifi et al. “The role of Bcl2 family of apoptosis regulator proteins in acute and chronic leukemias” describes the exciting new advances in understanding and targeting the Bcl-2 family of proteins and gives a comprehensive update on new agents that are in clinical studies targeting survival in acute and chronic leukemias. All of these three papers describe bona fide targets that are already subject to significant validation and commercial drug development. The seventh paper by P. Koehler et al. “Engineered T cells for the adoptive therapy of B cell-chronic lymphocytic leukemia (B-CLL)” in the issue addresses immunotherapy using T-cell therapies against CD19, which has recently been very successful and received widespread attention for treatment of chronic lymphocytic leukemia. This approach promises to provide sustained targeted therapy based on cell surface phenotype and although it has to deal with issues such as B-cell deficiency and intravenous immunoglobuin infusions, such approaches when combined with chemotherapy are very promising as a form of targeted gene-based therapy. In summary, the articles in this special issue address the spectrum of new targeted therapy development, from basic understandings of structure-function to mature rationale drugs already being tested in patients. We sought to cover the full spectrum of therapeutic development and are pleased to present a series of papers that do just that. As editors of this issue, we appreciate the important contributions of the authors of these review articles and hope that this issue will encourage expanded translational research toward developing novel therapies for hematologic malignancies. Kevin D. Bunting Cheng-Kui Qu Michael H. Tomasson

Chemotherapy for Advanced Gastric Cancer: Results from Western Clinical Trials

Current treatments for advanced gastric cancer are mainly palliative though the role of chemotherapy is evolving. Reference regimens vary, depending on the region and cultural preferences and in the United States, a combination of 5-fluorouracil and cisplatin is often used in untreated patients with advanced gastric cancer. There is a renewed interest in developing newer standards given the availability of novel agents including irinotecan, taxanes (paclitaxel and docetaxel), oxaliplatin and novel oral fluoropyrimidines like S-1. These have been used in the last five years either singly or in combination with promising results. We anticipate that with trials combining these agents, improved methodologies with appropriate endpoints, as well as the availability of molecular profiling techniques and a better understanding of molecular targets, we will be able to develop better treatments for patients with advanced gastric cancer.

Applied gene therapy in preclinical models of vascular injury.

Atherosclerosis remains the major cause of morbidity and mortality in Western countries. Atherothrombotic complications, including vascular occlusions and severe narrowing of nutrient blood vessels in the cerebral, coronary, or peripheral circulation, usually require invasive revascularization strategies. As molecular mediators contributing to these complications are being identified in more representative experimental injury models, and as gene transfer platforms and vectors acquire improved safety and efficacy profiles, there is ground for cautious optimism that gene-based interventions will likely reduce the clinical burden of these diseases. Increased generation of reactive oxygen species in diseased atherosclerotic vessels has been implicated in vasospasm, exaggerated neointima formation, and enhanced thrombosis. Ex vivo pressurized vascular gene transfer in venous bypass grafts using antisense oligonucleotides directed against cell-cycle control genes can modify the venous graft's phenotype and confer clinical benefit with improved long-term graft survival. Alternatively, percutaneous intra-arterial gene transfer is feasible, but at relatively low transgene expression levels. Although this may suffice in the case of secreted gene products with marked paracrine or bystander effects, including nitric oxide synthase and heme oxygenase-1, drug- and gene-eluting stents may provide the preferred future vehicle for well-controlled, quantifiable, and safe vascular gene transfer. Continued efforts to improve gene transfer technology in diseased human vessels and to increase our understanding of molecular targets are required before the full therapeutic potential of vascular gene therapy can be realized.