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Lung cancer remains the number one cause of cancer-related deaths worldwide with 221,200 estimated new cases and 158,040 estimated deaths in 2015. Approximately 80% of cases are non-small cell lung cancer (NSCLC). The diagnosis is usually made at an advanced stage where the prognosis is poor and therapeutic options are limited. The evolution of lung cancer is a multistep process involving genetic, epigenetic, and environmental factor interactions that result in the dysregulation of key oncogenes and tumor suppressor genes, culminating in activation of cancer-related signaling pathways. The past decade has witnessed the discovery of multiple molecular aberrations that drive lung cancer growth, among which are epidermal growth factor receptor (EGFR) mutations and translocations involving the anaplastic lymphoma kinase (ALK) gene. This has translated into therapeutic agent developments that target these molecular alterations. The absence of targetable mutations in 50% of NSCLC cases and targeted therapy resistance development underscores the importance for developing alternative therapeutic strategies for treating lung cancer. Among these strategies, pharmacologic modulation of the epigenome has been used to treat lung cancer. Epigenetics approaches may circumvent the problem of tumor heterogeneity by affecting the expression of multiple tumor suppression genes (TSGs), halting tumor growth and survival. Moreover, it may be effective for tumors that are not driven by currently recognized druggable mutations. This review summarizes the molecular pathology of lung cancer epigenetic aberrations and discusses current efforts to target the epigenome with different pharmacological approaches. Our main focus will be on hypomethylating agents, histone deacetylase (HDAC) inhibitors, microRNA modulations, and the role of novel epigenetic biomarkers. Last, we will address the challenges that face this old-new strategy in treating lung cancer.

Histiocytic sarcoma (HS) is an extremely rare non-Langerhans cell disorder with an aggressive course and limited treatment options. Recent advances in molecular/genetic sequencing have suggested a common clonal origin between various hematolymphoid disorders and cases of secondary HS. Deriving conclusions from previously reported cases of HS arising secondarily to certain hematolymphoid disorders, here we have tried to provide insight into the mechanisms influencing this evolution. We also discuss a clinical case of a 72-year-old man with a diagnosis of chronic myeloid leukemia (CML), presenting subsequently with a heterogeneous liver mass positive with a diagnosis of HS. The liver mass showed a retained BCR-ABL1 translocation suggesting clonality between the CML and HS. As seen in our case and other reported cases of HS derived secondarily, the concurrent expression of immunoglobulin heavy (IGH)-/lightchain rearrangements or cytogenetic markers common to the primary malignancy suggests an evolutionary mechanism involving lineage switching that could potentially be influenced by genetic or epigenetic cues which may occur at the level of a progenitor or the malignant cell itself. Clinical caseA 72-year-old male was brought to the emergency room with a one-month history of progressively worsening bilateral lower extremity swelling, more than 10 lbs. of weight loss, lack of appetite, and rapidly declining performance status. His past medical history was notable for CML, which was diagnosed 30 months prior to presentation (Fig. 1). The patient was treated on a protocol with imatinib (400 mg daily) and demonstrated a complete molecular response to tyrosine kinase inhibitor (TKI) therapy. Focused physical examination demonstrated an emaciated male in mild distress from abdominal pain, right upper quadrant tenderness on deep palpation, and abdominal distension without any signs of an acute abdomen.His peripheral blood smear revealed normochromic, normocytic anemia with hemoglobin of 7.6 g/dL (normal range, 12.5-16.3 g/dL), a white blood count of 7 730/lL (normal range, 3 600-11 200/lL), a red blood cell count of 2.78 M/lL (normal range 4.06-5.63 M/lL), and a platelet count of 114 000/lL (normal range, 159 000-386 000/lL). Serum iron was low (21 lg/dL) with a low TIBC (216 lg/dL), which was attributed to anemia of chronic disease. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed the absence of the BCR/ABL transcript in the peripheral blood.Computed tomography scan of the chest and abdomen revealed a large, complex, heterogeneous, hypodense mass involving nearly all of the caudate and left lobes of the liver. These lesions were not present in the previous examination carried out 1 year before.Biopsy of the liver mass revealed diffuse infiltration of large and irregular pleomorphic cells with lobulated nuclei with some binucleated and trinucleated cells containing

Cardiovascular disease (CVD) continues to be the leading cause of death in the world. Increased inflammation and an enhanced thrombotic milieu represent two major complications of CVD, which can culminate into an ischemic event. Treatment for these life-threatening complications remains reperfusion and restoration of blood flow. However, reperfusion strategies may result in ischemia–reperfusion injury (I/RI) secondary to various cardiovascular pathologies, including myocardial infarction and stroke, by furthering the inflammatory and thrombotic responses and delivering inflammatory mediators to the affected tissue. Annexin A1 (AnxA1) and its mimetic peptides are endogenous anti-inflammatory and pro-resolving mediators, known to have significant effects in resolving inflammation in a variety of disease models. Mounting evidence suggests that AnxA1, which interacts with the formyl peptide receptor (FPR) family, may have a significant role in mitigating I/RI associated complications. In this review article, we focus on how AnxA1 plays a protective role in the I/R based vascular pathologies.

Neutrophils plays a crucial role in the intertwined processes of thrombosis and inflammation. Altered neutrophil phenotype may contribute to inadequate resolution which is known to be a major pathophysiological contributor of thrombo-inflammatory conditions such as Sickle Cell Disease (SCD). The endogenous protein Annexin A1 (AnxA1) facilitates inflammation resolution via Formyl Peptide Receptors (FPRs). We sought to comprehensively elucidate the functional significance of targeting neutrophil dependent AnxA1/FPR2/ALX pathway in SCD. Administration of AnxA1 mimetic peptide AnxA1Ac2-26 ameliorated cerebral thrombotic responses in Sickle transgenic mice via regulation of FPR2/ALX (a fundamental receptor involved in resolution) pathway. We demonstrated direct evidence that neutrophils with SCD phenotype play a key role in contributing to thrombo-inflammation. In addition, AnxA1Ac2-26 regulated activated SCD neutrophils through protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2) to enable resolution. Herein, we present compelling conceptual evidence that targeting the AnxA1/FPR2/ALX pathway may provide new therapeutic possibilities against thrombo-inflammatory conditions such as SCD.