Nanomedicine as a putative approach for active targeting of hepatocellular carcinoma.

The effectiveness of chemotherapy in hepatocellular carcinoma (HCC) is restricted by chemo-resistance and systemic side effects. To improve the efficacy and safety of chemotherapeutics in HCC management, scientists have attempted to deliver these drugs to malignant tissues using targeted carriers as nanoparticles (NPs). Among the three types of NPs targeting (active, passive, and stimuli-responsive), active targeting is the most commonly investigated in HCC treatment. Despite the observed promising results so far, clinical research on nanomedicine targeting for HCC treatment still faces many challenges.These include batch-to-batch physicochemical properties' variations, limiting large scale production and insufficient data on human and environmental toxicities. This review summarized the characteristics of different nanocarriers, ligands, targeted receptors on HCC cells and provided recommendations to overcome the challenges, facing this novel line of treatment for HCC.

Novel therapeutic strategies for spinal osteosarcomas.

At the dawn of the third millennium, cancer has become the bane of twenty-first century man, and remains a predominant public health burden, affecting welfare and life expectancy globally. Spinal osteogenic sarcoma, a primary spinal malignant tumor, is a rare and challenging neoplastic disease to treat. After the conventional therapeutic modalities of chemotherapy, radiation and surgery have been exhausted, there is currently no available alternative therapy in managing cases of spinal osteosarcoma. The defining signatures of tumor survival are characterised by cancer cell ability to stonewall immunogenic attrition and apoptosis by various means. Some of these biomarkers, namely immune-checkpoints, have recently been exploited as druggable targets in osteosarcoma and many other different cancers. These promising strides made by the use of reinvigorated immunotherapeutic approaches may lead to significant reduction in spinal osteosarcoma disease burden and corresponding reciprocity in increase of survival rates. In this review, we provide the background to spinal osteosarcoma, and proceed to elaborate on contribution of the complex ecology within tumor microenvironment giving arise to cancerous immune escape, which is currently receiving considerable attention. We follow this section on the tumor microenvironment by a brief history of cancer immunity. Also, we draw on the current knowledge of treatment gained from incidences of osteosarcoma at other locations of the skeleton (long bones of the extremities in close proximity to the metaphyseal growth plates) to make a case for application of immunity-based tools, such as immune-checkpoint inhibitors and vaccines, and draw attention to adverse upshots of immune-checkpoint blockers as well. Finally, we describe the novel biotechnique of CRISPR/Cas9 that will assist in treatment approaches for personalized medication.

Current Understanding of Human Metaproteome Association and Modulation.

During the last decade, metaproteomics has provided a better understanding and functional characterization of the microbiome. A large body of evidence now reveals interspecies, species of bacteria-host interactions, via the secreted modulatory microbial protein "metaproteome". Although high-throughput state-of-art mass spectrometry has recently empowered metaproteomics, its profile remains unclear, and, most importantly, the exact consequences and underlying mechanism of these protein molecules on the host are insufficiently understood. Here we address the current progress in the study of the human metaproteome, suggesting possible modulation, a metaproteome dysbiotic signature, challenges, and future perspectives.

A shared comparison of diabetes mellitus and neurodegenerative disorders.

Diabetes mellitus (DM), one of the most prevalent metabolic diseases in the world population, is associated with a number of comorbid conditions including obesity, pancreatic endocrine changes, and renal and cardio-cerebrovascular alterations, coupled with peripheral neuropathy and neurodegenerative disease, some of these disorders are bundled into metabolic syndrome. Type 1 DM (T1DM) is an autoimmune disease that destroys the insulin-secreting islet cells. Type 2 DM (T2DM) is diabetes that is associated with an imbalance in the glucagon/insulin homeostasis that leads to the formation of amyloid deposits in the brain, pancreatic islet cells, and possibly in the kidney glomerulus. There are several layers of molecular pathologic alterations that contribute to the DM metabolic pathophysiology and its associated neuropathic manifestations. In this review, we describe the general signature metabolic features of DM and the cross-talk with neurodegeneration. We will assess the underlying molecular key players associated with DM-induced neuropathic disorders that are associated with both T1DM and T2DM. In this context, we will highlight the role of tau and amyloid protein deposits in the brain as well in the pancreatic islet cells, and possibly in the kidney glomerulus. Furthermore, we will discuss the central role of mitochondria, oxidative stress, and the unfolded protein response in mediating the DM-associated neuropathic degeneration. This study will elucidate the relationship between DM and neurodegeneration which may account for the evolution of other neurodegenerative diseases, particularly Alzheimer's disease and Parkinson's disease as discussed later.

Cytoskeletal remodeling and regulation of cell fate in the hypertensive neonatal pulmonary artery in response to stress.

Neonatal pulmonary hypertension (PHN) is a lethal progressive disease that occurs in prenatal circulatory transition. Mechanical wall strain caused by cardiac pulsation integrates with hypoxia to generate rapidly progressive myocyte cytoskeleton disassembly and failure to exert force generation. The physiological responses to such an interaction have not been investigated. The persistent phenotype does not respond to traditional vasodilator therapy; hence, there is a need for new treatment strategies to improve the morbidity and mortality outcomes. We reviewed the current research methods, models, and markers of persistent PHN relevant to oxidative and nitrosative stress as well as cell fate commitment, with an emphasis on apoptosis and proliferation. We surveyed potential investigations into the role of senescence in neonatal PHN cell fate decision programming during vasodilator treatment and suggested putative drug targets to improve clinical outcomes. We identified important signaling intermediates of senescence and cell cycle entry regulation in hypertensive pulmonary arterial tissues.

What role does the stress response have in congestive heart failure?

This review is concerned with cardiac malfunction as a result of an imbalance in protein proteostasis, the homeostatic balance between protein removal and regeneration in a long remodeling process involving the endoplasmic reticulum (ER) and the unfolded protein response (UPR). The importance of this is of special significance with regard to cardiac function as a high energy requiring muscular organ that has a high oxygen requirement and is highly dependent on mitochondria. The importance of mitochondria is not only concerned with high energy dependence on mitochondrial electron transport, but it also has a role in the signaling between the mitochondria and the ER under stress. Proteins made in the ER are folded as a result of sulfhydryl groups (-SH) and attractive and repulsive reactions in the tertiary structure. We discuss how this matters with respect to an imbalance between muscle breakdown and repair in a stressful environment, especially as a result of oxidative and nitrosative byproducts of mitochondrial activity. The normal repair is a remodeling, but under this circumstance, the cell undergoes or even lysosomal "self eating" autophagy, or even necrosis instead of apoptosis. We shall discuss the relationship of the UPR pathway to chronic congestive heart failure (CHF).

A shared comparison of diabetes mellitus and neurodegenerative disorders.

Diabetes mellitus (DM) is one of the most common diseases in the world population, associated with obesity, pancreatic endocrine changes, cardiovascular disease, renal glomerular disease, cerebrovascular disease, peripheral neuropathy, neurodegenerative disease, retinal disease, sleep apnea, some of which are bundled into the metabolic syndrome. The main characteristic of this disease is hyperglycemia, and often with albuminuria. Nevertheless, the classic features, with ketoacidosis in the extreme, are only a first layer of description of this condition. The description of the islet cells of the endocrine pancreas was first described by Opie, and the discovery of insulin by tying off the exocrine pancreatic ducts followed. We later find that the ß-cells secrete insulin and glucagon, which synchronously stimulate or suppress glycogenolysis, and that insulin is essential for glucose intake into the cell. There are yet two other layers for our understanding of diabetes and the effects of its dysfunction, which is the basis for understanding the system-wide expression of the disease. We describe the molecular basis for the central nervous system neuropathic diseases that are associated with both Type 1 DM (T1DM) and Type 2 DM (T2DM), but more so with T2DM. T2DM is an autoimmune disease that destroys the insulin secreting islet cells. T2DM is the diabetes that is associated with an imbalance in the glucagon/insulin homeostasis that leads to the formation of amyloid deposits in the brain, pancreatic islet cells, and possibly the kidney glomerulus.

New approach to differentiate primary from latent Toxoplasma gondii abortion through immunoglobulin and DNA interpretation.

BACKGROUND: Toxoplasma gondii is an acute or latent zoonotic abortifacient human protozoan. Women may be aborted due to recent or latent infection during pregnancy or order to flare up of the dormant bradyzoites to acute tachyzoites (latent opportunistic relapse). AIMS: 1) to validate the interpretation of IgM and IgG immunoglobulins seromonotoring with DNA comparative results in differentiating recent from latent T. gondii abortion. METHOD: Blood with the corresponding placental or uterine wash samples were collected from 73 aborted Egyptian women from Cairo and Giza labour wards. Patients aborted in any of the phases (Ph-1, Ph-2, Ph-3 and Ph-4 were corresponding to abortion at the 1st, 2nd and 3rd trimesters plus females who gave birth with congenital anomalies), respectively. All aborted patients were assayed serologically by Enzyme Linked Immunosorbent Assay (ELISA) for IgM and IgG titers and the compatible DNA from placenta and uterine wash tissues by conventional Polymerase Chain Reaction (PCR) specific for T. gondii. RESULTS: Sero-positive aborted women were 50.7% by ELISA versus 37% by PCR. Not all T. gondii sero-positive aborted women were having T. gondii DNA or harboring compatible placental T. gondii cysts. This denotes that immunoglobulins alone are insufficient criteria for confirming toxoplasma abortion. CONCLUSION: Immunoglobulins with DNA comparative results can possibly differentiate recent from latent T. gondii abortion at higher precision. We recommend the need for routine monitoring of T. gondii i.e. (pre-, during and post-delivery).

Endocrine Imbalance Associated With Proteome Changes in Diabetes.

The dynamics of cellular metabolism involves rapid interactions between proteins and nucleic acids, proteins and proteins, and signaling. These involve the interactions with respect to the sulfur bond, noncovalent electrostatic interactions, protein structure stabilization and protein-ligand binding, weak electrostatic interactions in proteins, oxygen radicals that initiate a change in conformation and a chain of events. We review a development in molecular medicine that is a very promising work in progress. We also review the current and future research methods involving mitochondria. Long-term effects of diabetes include glycation of proteins, for example, glycohemoglobin (HbA1c), increased risk of cardiovascular diseases, atherosclerosis, retinopathy, nephropathy, and neurological dysfunctions. Tissues are exposed to significant quantities of highly reactive chemical species including nitric oxide • NO and reactive oxygen species ROS over months to years, to an extent generated by mitochondrial activities. The reactions of • NO can be broadly discussed with reference to three main processes which control their fate in biological systems: (1) diffusion and intra-cellular consumption; (2) autooxidation to form nitrous anhydride N2 O3 ; and (3) reaction with superoxide O2• - to form peroxynitrite ONOO-. Reactive nitrogen species produced by macrophages and neutrophils in the interstitial space, with emphasis on • NO, N2 O3 , ONOO-, and nitrogen dioxide radicals • NO2 generate protein and DNA damage. Serum thiol (-SH) groups act as an important extracellular scavenger of peroxides and are therefore helpful in protecting the surrounding tissues. The events described here are a homeostatic endocrine imbalance that is associated with proteostasis. The advances we have seen in untangling this web of interactions are sure to continue at a breathtaking pace. J. Cell. Biochem. 118: 3569-3576, 2017. © 2017 Wiley Periodicals, Inc.

The transcriptome of nitrofen-induced pulmonary hypoplasia in the rat model of congenital diaphragmatic hernia.

BACKGROUND: We currently do not know how the herbicide nitrofen induces lung hypoplasia and congenital diaphragmatic hernia in rats. Our aim was to compare the differentially expressed transcriptome of nitrofen-induced hypoplastic lungs to control lungs in embryonic day 13 rat embryos before the development of embryonic diaphragmatic defects. METHODS: Using next-generation sequencing technology, we identified the expression profile of microRNA (miRNA) and mRNA genes. Once the dataset was validated by both RT-qPCR and digital-PCR, we conducted gene ontology, miRNA target analysis, and orthologous miRNA sequence matching for the deregulated miRNAs in silico. RESULTS: Our study identified 186 known mRNA and 100 miRNAs which were differentially expressed in nitrofen-induced hypoplastic lungs. Sixty-four rat miRNAs homologous to known human miRNAs were identified. A subset of these genes may promote lung hypoplasia in rat and/or human, and we discuss their associations. Potential miRNA pathways relevant to nitrofen-induced lung hypoplasia include PI3K, TGF-ß, and cell cycle kinases. CONCLUSION: Nitrofen-induced hypoplastic lungs have an abnormal transcriptome that may lead to impaired development.

New insights into lung development and diseases: the role of microRNAs.

MicroRNAs (miRNAs) are short endogenous noncoding RNA molecules (∼ 22 nucleotides) that can regulate gene expression at the post-transcription level. Research interest in the role of miRNAs in lung biology is emerging. MiRNAs have been implicated in a range of processes such as development, homeostasis, and inflammatory diseases in lung tissues and are capable of inducing differentiation, morphogenesis, and apoptosis. In recent years, several studies have reported that miRNAs are differentially regulated in lung development and lung diseases in response to epigenetic changes, providing new insights for their versatile role in various physiological and pathological processes in the lung. In this review, we discuss the contribution of miRNAs to lung development and diseases and possible future implications in the field of lung biology.

Beneficial Outcomes of Cancer Therapeutic Modalities Based on Targeting Apoptosis.

BACKGROUND: In the clinical setting, anticancer therapy is routinely administered to stimulate programmed cell death or "apoptosis." The goal is to eliminate tumor cells. Whether selective activation of apoptosis facilitates aggressive disease relapse in the longer term is still unaddressed. Apoptosis defects have a crucial role in cancer progression and carcinogenesis. Thus, targeting apoptosis may be important in developing new cancer therapeutic modalities. METHODS: We summarize the shift in thinking that, while apoptosis is a barrier to oncogenesis, it paradoxically drives cancer formation and progression when executed incompletely, i.e., sublethal apoptosis. Also, we review apoptotic mechanisms, the role of apoptosis in carcinogenesis, and how it contributes to cancer treatment. RESULT AND CONCLUSION: Most current research focuses on the extent of cell death in vitro, but no evidence exists that protein regulation of cell death in vitro is similar to what happens in vivo. Future research requires identifying targets upstream and downstream of such proteins through identifying protein-protein interactions in different survival/apoptosis pathways. Finding nexuses where such pathways interconnect is critical, along with possible mechanisms for regulation.

Protein networks linking Warburg and reverse Warburg effects to cancer cell metabolism.

It was 80 years after the Otto Warburg discovery of aerobic glycolysis, a major hallmark in the understanding of cancer. The Warburg effect is the preference of cancer cell for glycolysis that produces lactate even when sufficient oxygen is provided. "reverse Warburg effect" refers to the interstitial tissue communications with adjacent epithelium, that in the process of carcinogenesis, is needed to be explored. Among these cell-cell communications, the contact between epithelial cells; between epithelial cells and matrix; and between fibroblasts and inflammatory cells in the underlying matrix. Cancer involves dysregulation of Warburg and reverse Warburg cellular metabolic pathways. How these gene and protein-based regulatory mechanisms have functioned has been the basis for this review. The importance of the Warburg in oxidative phosphorylation suppression, with increased glycolysis in cancer growth and proliferation is emphasized. Studies that are directed at pathways that would be expected to shift cell metabolism to an increased oxidation and to a decrease in glycolysis are emphasized. Key enzymes required for oxidative phosphorylation, and affect the inhibition of fatty acid metabolism and glutamine dependence are conferred. The findings are of special interest to cancer pharmacotherapy. Studies described in this review are concerned with the effects of therapeutic modalities that are intimately related to the Warburg effect. These interactions described may be helpful as adjuvant therapy in controlling the process of proliferation and metastasis.

Diagnosis and Management of Hematological Adverse Events Induced by Immune Checkpoint Inhibitors: A Systematic Review.

There has been less volume of literature focusing on the Immune-related Hematological Adverse Drug Events (Hem-irAEs) of Immune Checkpoint Inhibitors (ICPis) in cancer patients. Furthermore, there has been no consensus about the management of hematological toxicity from immunotherapy in the recently published practice guidelines by the European Society for Medical Oncology (ESMO). We conducted a systematic review of case reports/series to describe the diagnosis and management of potentially rare and unrecognized Hem-irAEs. We searched Medline, OVID, Web of Science for eligible articles. Data were extracted on patient characteristics, Hem-irAEs, and management strategies. We performed quality assessment using the Pierson-5 evaluation scheme and causality assessment using the Naranjo scale. Our search retrieved 49 articles that described 118 cases. The majority of patients had melanoma (57.6%) and lung cancer (26.3%). The most common Hem-irAEs reported with ICPis (such as nivolumab, ipilimumab, and pembrolizumab) were thrombocytopenia, hemolytic and aplastic anemias. Less reported adverse events included agranulocytosis and neutropenia. Steroids were commonly used to treat these adverse events with frequent success. Other used strategies included intravenous immunoglobulins (IVIG), rituximab, and transfusion of blood components. The findings of this review provide more insights into the diagnosis and management of the rarely reported Hem-irAEs of ICPis.

Correction: Application of laser scanning cytometry in vascular smooth muscle remodeling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Insights into the Role of DNA Methylation and Protein Misfolding in Diabetes Mellitus.

BACKGROUND: Diabetes mellitus is a metabolic disorder that is characterized by impaired glucose tolerance resulting from defects in insulin secretion, insulin action, or both. Epigenetic modifications, which are defined as inherited changes in gene expression that occur without changes in gene sequence, are involved in the etiology of diabetes. METHODS: In this review, we focused on the role of DNA methylation and protein misfolding and their contribution to the development of both type 1 and type 2 diabetes mellitus. RESULTS: Changes in DNA methylation in particular are highly associated with the development of diabetes. Protein function is dependent on their proper folding in the endoplasmic reticulum. Defective protein folding and consequently their functions have also been reported to play a role. Early treatment of diabetes has proven to be of great benefit, as even transient hyperglycemia may lead to pathological effects and complications later on. This has been explained by the theory of the development of a metabolic memory in diabetes. The basis for this metabolic memory was attributed to oxidative stress, chronic inflammation, non-enzymatic glycation of proteins and importantly, epigenetic changes. This highlights the importance of linking new therapeutics targeting epigenetic mechanisms with traditional antidiabetic drugs. CONCLUSION: Although new data is evolving on the relation between DNA methylation, protein misfolding, and the etiology of diabetes, more studies are required for developing new relevant diagnostics and therapeutics.

Significance of Glypican-3 in Early Detection of Hepatocellular Carcinoma in Cirrhotic Patients.

BACKGROUND: Egypt has high incidence of hepatocellular carcinoma (HCC). This is due to wide spread of hepatitis C virus (HCV) infection which is responsible for most of the cases of liver cirrhosis. The major diagnostic techniques for HCC include serum markers and various imaging modalities. Glypican 3 (GPC3) protein is highly expressed in HCC, but not in normal liver tissue. The significance of GPC3 as a predictor or diagnostic tool for human tumors other than HCC is unclear. AIM: To quantitatively assess the role of GPC3 in diagnosis of HCC in comparison to α-fetoprotein (AFP), ultrasonography (US), and computerized tomography (CT). PATIENTS AND METHODS: This cross-sectional study enrolled 85 subjects: 40 cirrhotic patients with primary HCC, 30 cirrhotic patients without HCC, and 15 healthy individuals. All patients were recruited from the Gastroenterology and Tropical Departments and outpatient clinics of New Damietta Hospital during the period from November 2010 to August 2012. RESULTS: GPC3 is positive in some HCC patients with normal levels of AFP. AFP has lower sensitivity (67.5%) compared to higher sensitivity of GPC3 (82.5%), and near specificity (61.2%) to GPC3 (57.8%). CONCLUSION AND SIGNIFICANCE: The combined serum AFP and GPC3 significantly increased the sensitivity of HCC diagnosis. Although GPC3 is better than AFP in diagnosis of HCC, it still lacks the 100% sensitivity and specificity because some patients have negative or normal level of GPC3 (below the cutoff point 1.5 ng/ml) despite being diagnosed by triphasic CT.

Evaluation of Fecal M2PK as a Diagnostic Marker in Colorectal Cancer.

BACKGROUND: Invasive colonoscopy is the gold standard for patients at risk for colorectal cancer. However, the need for non-invasive and specific markers is required. OBJECTIVE: To evaluate the sensitivity of the glycolytic pyruvate kinase isoenzyme type M2 dimer (M2PK) as a diagnostic biomarker for colorectal cancer (CRC) and adenomatous colorectal polyps (CRP) screening. DESIGN: Case-control. PATIENTS: Twenty patients with CRC, 20 patients with CRP (lack criteria for colonic cancer by biopsy), and 20 normal subjects. OUTCOME: Complete blood count (CBC), erythrocyte sedimentation rate (ESR), tumor markers: carcino embryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), fecal occult blood test (FOBT), and fecal M2PK. Pelvic and abdominal ultrasound (US), colonoscopy, and a histopathological examination. RESULTS: Only weight loss and cachexia were significantly associated with CRC than CRP or control groups. M2PK was the most sensitive and specific test in differentiating CRC from CRP and the control subjects (sensitivity = 75%, specificity = 100%). LIMITATIONS: (1) The selection of cases for three well-matched groups, as to perform colonoscopy in well-prepared cases and conditions. (2) Replicates in more than 20 cases for confirmation at the expense of enrolling new patients. (3) The cost associated with tumor markers analysis. CONCLUSION: Fecal M2PK can be used as a precolonoscopy screening test for CRC patients, and is superior to other tumor markers, and in indicating the progress of colorectal adenomas > 1 cm. Thus being cost-effective and easy-to-perform test, it is a feasible tool to preselect patients who require colonoscopy.

Fib-4 Predicts Early Hematological Adverse Events Induced by Interferon-Based Triple Therapy in Chronic Hepatitis C Virus Patients.

Interferon-alpha (IFN-α)-based therapy is associated with several hematological adverse events in hepatitis C virus (HCV)-infected patients with advanced fibrosis. We performed this study to evaluate the association between Fibrosis-4 (Fib-4) index and hematological adverse events in patients with chronic HCV infection, undergoing IFN-α-based triple therapy. We included 120 HCV-infected patients, receiving triple therapy: weekly PegIFN-α, daily ribavirin (1,000-1,200 mg), and daily sofosbuvir (400 mg) for 12 weeks. We compared Fib-4 scores for patients who developed hematological adverse events at weeks 4 (w4) and w12 of treatment and w12 post-treatment versus those who did not. Treatment with the aforementioned triple regimen was associated with a sustained virological response (SVR)-12 rate of 93.9%. We found no significant associations (P > 0.05) between SVR12 rate and the degree of fibrosis or the risk of hematological adverse events. The Fib-4 score could predict patients who developed hematological adverse events (anemia, leukopenia, and neutropenia) in the first month of treatment, but not in later stages. A Fib-4 cutoff value of 3.59 had high specificity for anemia, leukopenia, and neutropenia (85.1%, 87.2%, and 88.2%, respectively), but had low sensitivity for detecting the 3 events. In conclusion, the Fib-4 score may predict early hematological adverse effects in HCV-infected patients on IFN-based triple therapy.

Diabetes-induced Proteome Changes Throughout Development.

BACKGROUND: Diabetes Mellitus (DM) is a multisystemic disease involving the homeostasis of insulin secretion by the pancreatic islet beta cells (ß-cells). It is associated with hypertension, renal disease, and arterial and arteriolar vascular diseases. DISCUSSION: The classification of diabetes is identified as type 1 (gene linked ß-cell destruction in childhood) and type 2 (late onset associated with ß-cell overload and insulin resistance in peripheral tissues. Type 1 diabetes is characterized by insulin deficiency, type 2 diabetes by both insulin deficiency and insulin resistance. The former is a genetically programmed loss of insulin secretion whereas the latter constitutes a disruption of the homeostatic relationship between the opposing activity of ß- cell insulin and alpha cell (α-cell) glucagon of the Islets of Langerhans. The condition could also occur in pregnancy, as a prenatal occurring event, possibly triggered by the hormonal changes of pregnancy combined with ß-cell overload. This review discusses the molecular basis of the biomolecular changes that occur with respect to glucose homeostasis and related diseases in DM. The underlying link between pancreatic, renal, and microvascular diseases in DM is based on oxidative stress and the Unfolded Protein Response (UPR). CONCLUSION: Studying proteome changes in diabetes can deepen our understanding of the biomolecular basis of disease and help us acquire more efficient therapies.