Mohamed I. Saad

Monash University (Australia) · Hudson Institute of Medical Research

Oncogenic KRAS mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC. In genetically engineered and xenograft (human cell line and patient-derived) KrasG12Ddriven LAC models, the specific bl...

Lung cancer is the leading cause of cancer-related mortality, with most cases attributed to tobacco smoking, in which nicotine-derived nitrosamine ketone (NNK) is the most potent lung carcinogen. The ADAM17 protease is responsible for the ectodomain shedding of many pro-tumourigenic cytokines, growth factors and receptors, and therefore is an attra...

Pulmonary emphysema is the major debilitating component of chronic obstructive pulmonary disease (COPD), which is a leading cause of morbidity and mortality worldwide. The ADAM17 protease mediates inflammation via ectodomain shedding of numerous pro-inflammatory cytokines, cytokine receptors and adhesion molecules, however, its role in the pathogen...

Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalization. Despite the global health burden of pancreatitis, currently, there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinas...

The protease A Disintegrin And Metalloproteinase 17 (ADAM17) plays a central role in the pathophysiology of several diseases. ADAM17 is involved in the cleavage and shedding of at least 80 known membrane-tethered proteins, which subsequently modulate several intracellular signaling pathways, and therefore alter cell behavior. Dysregulated expressio...

Acute pancreatitis is a serious inflammatory disease of the pancreas that can lead to lung injury. Despite extensive research, the mechanisms underlying this complication are ill-defined. In recent years, in vitro co-culture systems have emerged as powerful tools for studying complex interactions between different cell types in disease. In the cont...

Pulmonary emphysema is associated with dysregulated innate immune responses that promote chronic pulmonary inflammation and alveolar apoptosis, culminating in lung destruction. However, the molecular regulators of innate immunity that promote emphysema are ill-defined. Here, we investigated whether innate immune inflammasome complexes, comprising t...

The oncogenic potential of the latent transcription factor signal transducer and activator of transcription (STAT)3 in many human cancers, including lung cancer, has been largely attributed to its nuclear activity as a tyrosine-phosphorylated (pY705 site) transcription factor. By contrast, an alternate mitochondrial pool of serine phosphorylated (p...

Objective The absent in melanoma 2 (AIM2) cytosolic pattern recognition receptor and DNA sensor promotes the pathogenesis of autoimmune and chronic inflammatory diseases via caspase-1-containing inflammasome complexes. However, the role of AIM2 in cancer is ill-defined. Design The expression of AIM2 and its clinical significance was assessed in hu...

Tumour-associated neutrophils (TANs) can support tumour growth by suppressing cytotoxic lymphocytes. AT-RvD1 is an eicosanoid that can antagonise neutrophil trafficking instigated by ALX/FPR2 ligands such as serum amyloid A (SAA). We aimed to establish whether SAA and ALOX5 expression associates with TANs and investigate the immunomodulatory action...

Chronic lung diseases including asthma, chronic obstructive pulmonary disease (COPD) and lung fibrosis represent a major burden on healthcare systems with limited effective therapeutic options. Developing effective treatments for these debilitating diseases requires an understanding of how alterations at the molecular level affect lung macroscopic...

Patient-derived xenografts (PDXs) are created by implanting human tumor tissue or cells into immunodeficent mice, and enable the study of tumor biology, biomarkers and response to therapy in vivo. This chapter describes a method for lung adenocarcinoma (LAC) PDX generation using subcutaneous implantation of tumor tissue and cell suspensions and inc...

There is growing appreciation of the role of lung stem/progenitor cells in the development and perpetuation of chronic lung disease including idiopathic pulmonary fibrosis. Human amniotic epithelial cells (hAECs) were previously shown to improve lung architecture in bleomycin induced lung injury, with further suggestion that hAECs obtained from ter...

Gastric cancer is associated with chronic inflammation (gastritis) triggered by infection with the Helicobacter pylori (H. pylori) bacterium. Elevated tyrosine phosphorylation (pY) of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and is aligned to nuclear transcriptional activity. By con...

Deregulated activation of the latent oncogenic transcription factor STAT3 in many human epithelial malignancies, including gastric cancer, has invariably been associated with its canonical tyrosine phosphorylation and enhanced transcriptional activity. By contrast, serine phosphorylation (pS) of STAT3 can augment its nuclear transcriptional activit...

Lung cancer is the leading cause of cancer-related mortality, which histologically is classified into small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancer diagnoses, with the majority of patients presenting with lung adenocarcinoma (LAC). KRAS mutations are a major driver of L...

Lung adenocarcinoma is the most common form of lung cancer, the leading cause of cancer death worldwide. Mutations in the KRAS gene are the most studied causes of lung adenocarcinoma. However, the development of specific drugs inhibiting KRAS has proven challenging, and there is now a pressing need to identify new ways to inhibit KRAS. Using a seri...

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Quantitative data on lung structure, such as volume, surface area and length, are used for assessment of the functional performance of the lung during normal development and inflammatory-related diseases such as chronic obstructive pulmonary disorder (COPD), and carcinogenesis, in animal models. Stereology is considered as the gold standard to obta...

Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammation, severe scarring, and stem cell senescence. Stem cell-based therapies modulate inflammatory and fibrogenic pathways by release of soluble factors. Stem cell-derived extracellular vesicles should be explored as a potential therapy for IPF. Human amnion epithelial cell-deriv...

Background: Hepatic stellate cells (HSCs) are the primary collagen-secreting cells in the liver. While HSCs are the major cell type involved in the pathogenesis of liver fibrosis, hepatic macrophages also play an important role in mediating fibrogenesis and fibrosis resolution. Previously, we observed a reduction in HSC activation, proliferation an...

Particle quantitation of hAEC-EVDM was performed by nanoparticle tracking analysis.

Lung adenocarcinoma (LAC) accounts for approximately 40% of all lung cancers, the leading cause of cancer death worldwide. Oncogenic Kras mutations are a common feature of LAC, although the identity of signaling networks which engage Kras to promote LAC remains ill-defined. Moreover, LAC is characterised by dysregulated inflammatory responses, whic...

Background: Human amnion epithelial cells (hAECs) are clonogenic and have been proposed to reduce inflammatory-induced tissue injury. Perturbation of the immune response is implicated in the pathogenesis of perinatal brain injury; modulating this response could thus be a novel therapy for treating or preventing such injury. The immunomodulatory pr...

Background Intrauterine environment plays a pivotal role in the origin of fatal diseases such as the metabolic syndrome. Diabetes is associated with low-grade inflammatory state and dysregulated adipokines production. The aim of this study is to investigate the effect of maternal diabetes on adipocytokines (adiponectin, leptin and TNF-α) production...

The present study aimed to evaluate the changes in levels of different independent risk factors for vascular diseases in the rat offspring of maternal obesity and malnutrition as maternal health disturbances are thought to have direct consequences on the offspring health. The effect of postnatal diet on the offspring was also assessed. Three group...

Globally, more than 300 million people are asthmatics and this number has been estimated to become 400 million by 2025. Asthma is a chronic inflammatory condition, that although has no cure, it is treatable in most patients. The most common structural alterations in asthmatic airways include thickening of the epithelial and subepithelial layers, in...

Placenta is the major exchange surface between mother and fetus and plays a pivotal role in fetal development. A better understanding of the mechanisms by which diabetes alters placental function may allow better management of diabetes pregnancies. In this study, we attempt to investigate the effect of diabetic milieu with and without malformation...

Background: The hypothesis of fetal origins of adult disease states that early life events program the occurrence of significant adult diseases, including diabetes and obesity. Maternal diabetes is associated with general stress environment for developing fetus, and gestational diabetes is an independent risk factor for type 2 diabetes and metaboli...

Background: Transgenerational inheritance of various diseases and phenotypes has been demonstrated in diverse species and involves various epigenetic markers. Obesity and malnourishment are nutritional stresses that have effects on offspring through increasing their risk of diabetes and/or obesity. Obesity and malnourishment both affect glucose met...

Background: Intrauterine environment plays a pivotal role in the origin of fatal diseases such as diabetes. Diabetes and obesity are associated with low-grade inflammatory state and dysregulated adipokines production. This study aims to investigate the effect of maternal obesity and malnutrition on adipokines production (adiponectin, leptin and TNF...

The effect of in-utero environment on fetal health and survival is long-lasting, and this is known as the fetal origin hypothesis. The oxidative stress state during gestation could play a pivotal role in fetal programming and development of diseases such as diabetes. In this study, we investigated the effect of intra-uterine obesity and malnutritio...

Diabetes mellitus is a heterogeneous, multifactorial, chronic disease characterized by ‎hyperglycemia owing to insulin insufficiency and insulin resistance (IR). Recent ‎epidemiological studies showed that the diabetes epidemic affects 382 million people ‎worldwide in 2013, and this figure is expected to be 600 million people by 2035. Diabetes is ‎...

In recent years, cell-based therapies have gained great enthusiasm as a new therapeutic approach for ‎addressing many disorders. Many researchers have shown the roles of stem cells in replacing ‎damaged tissues and in providing extracellular factors that can promote endogenous cellular ‎replenishment. Also, stem cells are rich source of soluble fac...

Type 2 diabetes mellitus (T2DM) is among the leading causes of death in postmenopausal women. The disruption of ovarian function may contribute to the incidence of T2DM. The purpose of this study was to investigate the effects of ovariectomy and T2DM on glucose and lipid homeostasis, perilipin levels in adipose tissues – as a lipolytic regulator, a...

Type 2 diabetes mellitus (T2DM) is a group of metabolic disorders characterized by hyperglycemia owing to insulin resistance and/or insulin deficiency. Current theories of T2DM pathophysiology include a decline in β-cells function, a defect in insulin signaling pathways and a dysregulation of secretory function of adipocytes. This study aimed to in...

Introduction: T2DM is a group of metabolic disorders manifested by hyperglycemia as a result of insulin insufficiency and/or resistance. The main goal of antidiabetic therapies is to lower glucose levels, and therefore prevent development of diabetes complications. DPP-4 inhibitors (e.g. sitagliptin) are relatively new antidiabetic drugs which inhi...