Alteration in DNA methylation patterns: Epigenetic signatures in gastrointestinal cancers.

Abnormalities in epigenetic modifications can cause malignant transformations in cells, leading to cancers of the gastrointestinal (GI) tract, which accounts for 20% of all cancers worldwide. Among the epigenetic alterations, DNA hypomethylation is associated with genomic instability. In addition, CpG methylation and promoter hypermethylation have been recognized as biomarkers for different malignancies. In GI cancers, epigenetic alterations affect genes responsible for cell cycle control, DNA repair, apoptosis, and tumorigenic-specific signaling pathways. Understanding the pattern of alterations in DNA methylation in GI cancers could help scientists discover new molecular-based pharmaceutical treatments. This study highlights alterations in DNA methylation in GI cancers. Understanding epigenetic differences among GI cancers may improve targeted therapies and lead to the discovery of new diagnostic biomarkers.

A computational approach to design a multiepitope vaccine against H5N1 virus.

Since 1997, highly pathogenic avian influenza viruses, such as H5N1, have been recognized as a possible pandemic hazard to men and the poultry business. The rapid rate of mutation of H5N1 viruses makes the whole process of designing vaccines extremely challenging. Here, we used an in silico approach to design a multi-epitope vaccine against H5N1 influenza A virus using hemagglutinin (HA) and neuraminidase (NA) antigens. B-cell epitopes, Cytotoxic T lymphocyte (CTL) and Helper T lymphocyte (HTL) were predicted via IEDB, NetMHC-4 and NetMHCII-2.3 respectively. Two adjuvants consisting of Human ß-defensin-3 (HßD-3) along with pan HLA DR-binding epitope (PADRE) have been chosen to induce more immune response. Linkers including KK, AAY, HEYGAEALERAG, GPGPGPG and double EAAAK were utilized to link epitopes and adjuvants. This construct encodes a protein having 350 amino acids and 38.46 kDa molecular weight. Antigenicity of ~ 1, the allergenicity of non-allergen, toxicity of negative and solubility of appropriate were confirmed through Vaxigen, AllerTOP, ToxDL and DeepSoluE, respectively. The 3D structure of H5N1 was refined and validated with a Z-Score of - 0.87 and an overall Ramachandran of 99.7%. Docking analysis showed H5N1 could interact with TLR7 (docking score of - 374.08 and by 4 hydrogen bonds) and TLR8 (docking score of - 414.39 and by 3 hydrogen bonds). Molecular dynamics simulations results showed RMSD and RMSF of 0.25 nm and 0.2 for H5N1-TLR7 as well as RMSD and RMSF of 0.45 nm and 0.4 for H5N1-TLR8 complexes, respectively. Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) confirmed stability and continuity of interaction between H5N1-TLR7 with the total binding energy of - 29.97 kJ/mol and H5N1-TLR8 with the total binding energy of - 23.9 kJ/mol. Investigating immune response simulation predicted evidence of the ability to stimulate T and B cells of the immunity system that shows the merits of this H5N1 vaccine proposed candidate for clinical trials.

Emerging roles of miR-145 in gastrointestinal cancers: A new paradigm.

Gastrointestinal (GI) carcinomas are a group of cancers affecting the GI tract and digestive organs, such as the gastric, liver, bile ducts, pancreas, small intestine, esophagus, colon, and rectum. MicroRNAs (miRNAs) are small functional non-coding RNAs (ncRNAs) which are involved in regulating the expression of multiple target genes; mainly at the post-transcriptional level, via complementary binding to their 3'-untranslated region (3'-UTR). Increasing evidence has shown that miRNAs have critical roles in modulating of various physiological and pathological cellular processes and regulating the occurrence and development of human malignancies. Among them, miR-145 is recognized for its anti-oncogenic properties in various cancers, including GI cancers. MiR-145 has been implicated in diverse biological processes of cancers through the regulation of target genes or signaling, including, proliferation, differentiation, tumorigenesis, angiogenesis, apoptosis, metastasis, and therapy resistance. In this review, we have summarized the role of miR-145 in selected GI cancers and also its downstream molecules and cellular processes targets, which could lead to a better understanding of the miR-145 in these cancers. In conclusion, we reveal the potential diagnostic, prognostic, and therapeutic value of miR-145 in GI cancer, and hope to provide new ideas for its application as a biomarker as well as a therapeutic target for the treatment of these cancer.

Blood culture-negative infective endocarditis presenting with atypical dermatologic manifestation: A rare case report and review of the literature.

Infective endocarditis (IE) rarely presents with cutaneous manifestations due to earlier diagnosis and treatment. We present a case of middle-aged male patient presenting with an erythematous papular rash in the upper extremities and left knee, further progressing into painful ulcers with crusted and necrotic center in the arms and fingers. These cutaneous lesions were further followed by shaking chills and fever, which brought the patient to our hospital. Laboratory evaluation revealed elevated ESR (erythrocyte sedimentation rate) and C-reactive protein. Blood cultures taken were negative. Biopsy of the skin lesions were consistent with cutaneous leukocytoclastic vasculitis, and the gram smear revealed gram-positive cocci. The patient developed dyspnea and chest pain, which raised suspicion for IE. TEE (transesophageal echocardiography) demonstrated mild LV diastolic dysfunction, 1+ tricuspid valve regurgitation, mild mitral regurgitation, and vegetation-like lesions on the surface of mitral valve leaflets, consequently IE was confirmed. In conclusion, clinicians must look carefully for skin manifestations in cases with high likelihood of IE, even when other typical symptoms are absent.

Long non-coding RNAs and melanoma: From diagnosis to therapy.

Although extremely rare, malignant melanoma is the deadliest type of skin malignancy with the inherent capability to invade other organs and metastasize to distant tissues. In 2021, it was estimated that approximately 106,110 patients may have received the diagnosis of melanoma, with a mortality rate of 7180. Surgery remains the common choice for treatment in patients with melanoma. Despite many advances in the treatment of melanoma, some patients, such as those who have received cytotoxic chemotherapeutic and immunotherapic agents, a significant number of patients may show inadequate treatment response following initiating these treatments. Non-coding RNAs, including lncRNAs, have become recently popular and attracted the attention of many researchers to make new insights into the pathogenesis of many diseases, particularly malignancies. LncRNAs have been thoroughly investigated in multiple cancers such as melanoma and have been shown to play a major role in regulating various physiological and pathological cellular processes. Considering their core regulatory function, these non-coding RNAs may be appropriate candidates for melanoma patients' diagnosis, prognosis, and treatment. In this review, we will cover all the current literature available for lncRNAs in melanoma and will discuss their potential benefits as diagnostic and/or prognostic markers or potent therapeutic targets in the treatment of melanoma patients.

Cellular Conversations in Glioblastoma Progression, Diagnosis and Treatment.

Glioblastoma (GBM) is the most frequent malignancy among primary brain tumors in adults and one of the worst 5-year survival rates (< 7%) among all human cancers. Till now, treatments that target particular cell or intracellular metabolism have not improved patients' survival. GBM recruits healthy brain cells and subverts their processes to create a microenvironment that contributes to supporting tumor progression. This microenvironment encompasses a complex network in which malignant cells interact with each other and with normal and immune cells to promote tumor proliferation, angiogenesis, metastasis, immune suppression, and treatment resistance. Communication can be direct via cell-to-cell contact, mainly through adhesion molecules, tunneling nanotubes, gap junctions, or indirect by conventional paracrine signaling by cytokine, neurotransmitter, and extracellular vesicles. Understanding these communication routes could open up new avenues for the treatment of this lethal tumor. Hence, therapeutic approaches based on glioma cells` communication have recently drawn attention. This review summarizes recent findings on the crosstalk between glioblastoma cells and their tumor microenvironment, and the impact of this conversation on glioblastoma progression. We also discuss the mechanism of communication of glioma cells and their importance as therapeutic targets and diagnostic and prognostic biomarkers. Overall, understanding the biological mechanism of specific interactions in the tumor microenvironment may help in predicting patient prognosis and developing novel therapeutic strategies to target GBM.

Retroperitoneal mesenchymal chondrosarcoma with metastasis to iliac vein: A rare case report and review of the literature.

The iliac vein is an extremely rare site of metastasis for extraskeletal mesenchymal chondrosarcoma (ESMC). Involvement of the veins usually leads to an extremely dismal prognosis. Here, we report a 50-year-old patient with retroperitoneal mesenchymal chondrosarcoma and initial metastasis to the iliac bone, which further progressed to involve the iliac vein. In this study, we reviewed the major characteristics of ESMC and the previously reported cases, considering the rarity of these tumors.

Non-coding RNAs and glioma: Focus on cancer stem cells.

Glioblastoma and gliomas can have a wide range of histopathologic subtypes. These heterogeneous histologic phenotypes originate from tumor cells with the distinct functions of tumorigenesis and self-renewal, called glioma stem cells (GSCs). GSCs are characterized based on multi-layered epigenetic mechanisms, which control the expression of many genes. This epigenetic regulatory mechanism is often based on functional non-coding RNAs (ncRNAs). ncRNAs have become increasingly important in the pathogenesis of human cancer and work as oncogenes or tumor suppressors to regulate carcinogenesis and progression. These RNAs by being involved in chromatin remodeling and modification, transcriptional regulation, and alternative splicing of pre-mRNA, as well as mRNA stability and protein translation, play a key role in tumor development and progression. Numerous studies have been performed to try to understand the dysregulation pattern of these ncRNAs in tumors and cancer stem cells (CSCs), which show robust differentiation and self-regeneration capacity. This review provides recent findings on the role of ncRNAs in glioma development and progression, particularly their effects on CSCs, thus accelerating the clinical implementation of ncRNAs as promising tumor biomarkers and therapeutic targets.

Virus, Exosome, and MicroRNA: New Insights into Autophagy.

Autophagy is known as a conserved self-eating mechanism that contributes to cells to degrade different intracellular components (i.e., macromolecular complexes, aggregated proteins, soluble proteins, organelles, and foreign bodies). Autophagy needs formation of a double-membrane structure, which is composed of the sequestered cytoplasmic contents, called autophagosome. There are a variety of internal and external factors involved in initiation and progression of autophagy process. Viruses as external factors are one of the particles that could be associated with different stages of this process. Viruses exert their functions via activation and/or inhibition of a wide range of cellular and molecular targets, which are involved in autophagy process. Besides viruses, a variety of cellular and molecular pathways that are activated and inhibited by several factors (e.g., genetics, epigenetics, and environment factors) are related to beginning and developing of autophagy mechanism. Exosomes and microRNAs have been emerged as novel and effective players anticipated in various stages of autophagy. More knowledge in these pathways and identification of accurate roles of them could help to provide better therapeutic approaches in several diseases such as cancer. We highlighted the roles of viruses, exosomes, and microRNAs in the autophagy processes.

Evidence for the Benefits of Melatonin in Cardiovascular Disease.

The pineal gland is a neuroendocrine gland which produces melatonin, a neuroendocrine hormone with critical physiological roles in the circadian rhythm and sleep-wake cycle. Melatonin has been shown to possess anti-oxidant activity and neuroprotective properties. Numerous studies have shown that melatonin has significant functions in cardiovascular disease, and may have anti-aging properties. The ability of melatonin to decrease primary hypertension needs to be more extensively evaluated. Melatonin has shown significant benefits in reducing cardiac pathology, and preventing the death of cardiac muscle in response to ischemia-reperfusion in rodent species. Moreover, melatonin may also prevent the hypertrophy of the heart muscle under some circumstances, which in turn would lessen the development of heart failure. Several currently used conventional drugs show cardiotoxicity as an adverse effect. Recent rodent studies have shown that melatonin acts as an anti-oxidant and is effective in suppressing heart damage mediated by pharmacologic drugs. Therefore, melatonin has been shown to have cardioprotective activity in multiple animal and human studies. Herein, we summarize the most established benefits of melatonin in the cardiovascular system with a focus on the molecular mechanisms of action.

Brucellosis presenting with sepsis and cholestasis: A rare presentation of an endemic disease with review of the literature.

Brucellosis is a zoonotic disease endemic to the Middle East and Mediterranean basin. It has gained diagnostic challenge recently due to its increasingly non-specific and vague manifestations at presentation. Here, we report a 53-year-old man presenting with undulating fever and shaking chills and frequency, dysuria, hesitancy and malodorous urine. He had prior complicated urinary tract infection treated with intravenous antibiotics. Further evaluation revealed negative urine culture, intra-hepatic cholestasis due to underlying infection, elevated acute phase reactants and pancytopenia.The diagnosis of brucella was established as blood cultures grew Brucella melitensis and serum serology for Brucellosis returned positive. Following initiation of anti- brucella drugs, fever and laboratory abnormalities gradually returned to normal. Brucellosis should be always considered in the differential diagnosis of patients presenting with sepsis in endemic regions or when empiric antibiotic therapy fails to improve clinical and laboratory abnormalities. Diagnosis requires high level of suspicious based on the clinical history and constellation of symptoms.

Ureterocele mimicking uterine polyp in a young woman presenting with a vulvar mass: A case report.

Ureterocele is a distal ureteral segment cystic dilatation. Its prevalence in women ranges from 1/5000 to 1/12000. A 22-year-old adult female presented with a vulvar tumor with left-side pain. She was a candidate for an interlabial lump biopsy. A vulvar growth mimicking a uterine polyp was identified during her further evaluation. On ultrasonography of the abdomen and pelvis, a left-sided hydronephrisis (grade 1), proximal ureteral dilatation, and a ureterocele related to the distal portion of the left ureter that protruded into the urethra were detected. Under anesthesia examination, the ureterocele was removed.

Application of Quercetin in the Treatment of Gastrointestinal Cancers.

Many cellular signaling pathways contribute to the regulation of cell proliferation, division, motility, and apoptosis. Deregulation of these pathways contributes to tumor cell initiation and tumor progression. Lately, significant attention has been focused on the use of natural products as a promising strategy in cancer treatment. Quercetin is a natural flavonol compound widely present in commonly consumed foods. Quercetin has shown significant inhibitory effects on tumor progression via various mechanisms of action. These include stimulating cell cycle arrest or/and apoptosis as well as its antioxidant properties. Herein, we summarize the therapeutic effects of quercetin in gastrointestinal cancers (pancreatic, gastric, colorectal, esophageal, hepatocellular, and oral).

Non-coding RNAs and glioblastoma: Insight into their roles in metastasis.

Glioma, also known as glioblastoma multiforme (GBM), is the most prevalent and most lethal primary brain tumor in adults. Gliomas are highly invasive tumors with the highest death rate among all primary brain malignancies. Metastasis occurs as the tumor cells spread from the site of origin to another site in the brain. Metastasis is a multifactorial process, which depends on alterations in metabolism, genetic mutations, and the cancer microenvironment. During recent years, the scientific study of non-coding RNAs (ncRNAs) has led to new insight into the molecular mechanisms involved in glioma. Many studies have reported that ncRNAs play major roles in many biological procedures connected with the development and progression of glioma. Long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) are all types of ncRNAs, which are commonly dysregulated in GBM. Dysregulation of ncRNAs can facilitate the invasion and metastasis of glioma. The present review highlights some ncRNAs that have been associated with metastasis in GBM. miRNAs, circRNAs, and lncRNAs are discussed in detail with respect to their relevant signaling pathways involved in metastasis.

The role of non-coding RNAs in chemotherapy for gastrointestinal cancers.

Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.

Neurofilament light chain as a biomarker for diagnosis of multiple sclerosis.

The treatments for multiple sclerosis (MS) have improved over the past 25 years, but now the main question for physicians is deciding who should receive treatment, for how long, and when to switch to other options. These decisions are typically based on treatment tolerance and a reasonable expectation of long-term efficacy. A significant unmet need is the lack of accurate laboratory measurements for diagnosis, and monitoring of treatment response, including deterioration and disease progression. There are few validated biomarkers for MS, and in practice, physicians employ two biomarkers discovered fifty years ago for MS diagnosis, often in combination with MRI scans. These biomarkers are intrathecal IgG and oligoclonal bands in the CSF (cerebrospinal fluid). Neurofilament light chain (NfL) is a relatively new biomarker for MS diagnosis and follow up. Neurofilaments are neuron-specific cytoskeleton proteins that can be measured in various body compartments. NfL is a new biomarker for MS that can be measured in serum samples, but this still needs further study to specify the laboratory cut-off values in clinical practice. In the present review we discuss the evidence for NfL as a reliable biomarker for the early detection and management of MS. Moreover, we highlight the correlation between MRI and NfL, and ask whether they can be combined.

Silymarin (milk thistle extract) as a therapeutic agent in gastrointestinal cancer.

Silymarin contains a group of closely-related flavonolignan compounds including silibinin, and is extracted from Silybum marianum species, also called milk thistle. Silymarin has been shown to protect the liver in both experimental models and clinical studies. The chemopreventive activity of silymarin has shown some efficacy against cancer both in vitro and in vivo. Silymarin can modulate apoptosis in vitro and survival in vivo, by interfering with the expression of cell cycle regulators and apoptosis-associated proteins. In addition to its anti-metastatic activity, silymarin has also been reported to exhibit anti-inflammatory activity. The chemoprotective effects of silymarin and silibinin (its major constituent) suggest they could be applied to reduce the side effects and increase the anti-cancer effects of chemotherapy and radiotherapy in various cancer types, especially in gastrointestinal cancers. This review examines the recent studies and summarizes the mechanistic pathways and down-stream targets of silymarin in the therapy of gastrointestinal cancer.