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Biological Chemistry

Controlling Epithelial to Mesenchymal Transition through Acetylation of Histone H2BK5


Author: Robert J. Mobley, Amy N. Abell

Manuscript ID: JNSCI#17-0728

Abstract:

Large-scale epigenetic changes take place when epithelial cells with cell-cell adhesion and apical-basal polarity transition into invasive, individual, mesenchymal cells through a process known as epithelial to mesenchymal transition (EMT). Importantly, cancers with stem cell properties disseminate and form distant metastases by reactivating the developmental EMT program. Recent studies have demonstrated that the epigenetic histone modification, H2BK5 acetylation (H2BK5Ac), is important in the regulation of EMT. For example, in trophoblast stem (TS) cells, H2BK5Ac promotes the expression of genes important to the maintenance of an epithelial phenotype. This finding lead to the discovery that TS cells and stem-like claudin-low breast cancer cells share similar H2BK5Ac-regulated gene expression linking developmental and cancer cell EMT. An improved understanding of the role of H2BK5Ac in developmental EMT and stemness will further our understanding of epigenetics in EMT-related pathologies. Here we examine the binders and regulators of H2BK5Ac and discuss the roles of H2BK5Ac in stemness and EMT.

 

Medical Sciences

The role of corneal stroma: A potential nutritional source for the cornea


Author: Lingling Zhang, Matthew C. Anderson, Chia-Yang Liu

Manuscript ID: JNSCI#17-0727

Abstract:

Corneal stroma plays a pivotal role in normal visual function.  Anatomically, it is located between the outer epithelium and the inner endothelium and is the thickest layer of the cornea. Keratocytes in the stroma produce a variety of cellular products, including growth factors/cytokines, extracellular matrix (ECM) components, and kinases. These products support normal corneal development and homeostasis. 

 

Immunology

Immune Mediator Pharmacogenomics: TCL1A SNPs and Estrogen-Dependent Regulation of Inflammation


Author: Ming-Fen Ho, Richard M. Weinshilboum

Manuscript ID: JNSCI#17-0701

Abstract:

This review describes the important functional implications of TCL1A single nucleotide polymorphisms (SNPs) discovered during pharmacogenomic studies of aromatase inhibitor-induced musculoskeletal adverse events that were subsequently shown to influence the expression of cytokines, chemokines, toll-like receptors (TLR) and NF-κB in a SNP and estrogen-dependent fashion. Functional genomic studies of these SNPs led to the discovery of novel mechanisms that may contribute to disease pathophysiology and which may also increase our understanding of pharmacogenomic aspects of regulation of the expression of inflammatory mediators. Specifically, TCL1A expression was induced by estrogens in a SNP-dependent fashion, resulting in downstream effects on the expression of immune mediators that included IL17RA, IL17A, CCR6, CCL20 TLR2, TLR7, TLR9, TLR10 and NF-κB, all of which have potential implications for inflammatory diseases such as rheumatoid arthritis—a disease for which two thirds of patients are women. Strikingly, this genomic phenomenon could be “reversed” by estrogen receptor antagonist treatment—once again in a SNP-dependent, i.e., in a pharmacogenomic fashion. Specifically, differential SNP-dependent effects on estrogen receptor binding to estrogen response elements before and after estrogen receptor blockade might be associated with mechanisms underlying the SNP genotype and estrogen-dependent regulation of TCL1A and the expression of downstream immune mediators. Furthermore, this SNP and estrogen-dependent phenotypic response can be “reversed” by SERM treatment. These observations could potentially open the way to understand, predict and even pharmacologically manipulate the expression of selected immune mediators in a SNP-dependent fashion.

 

Nutrition

Cancer Prevention and Treatment by Wholistic Nutrition


Author: T. Colin Campbell

Manuscript ID: JNSCI#17-0630

Abstract:

Cancer is traditionally considered a genetic disease. It starts with a gene mutation, often caused by environmental carcinogens that, upon enzymatic activation, covalently bind to DNA. If these carcinogen-DNA adducts escape repair, they result in a mutation, which is inherited by daughter cells and their subsequent progeny, while accumulating more mutations thought to advance cellular independence, metastasis, and drug resistance, among other characteristics, typically observed for advanced cancer. Initiating, promoting and progressing cancer by mutations infers irreversibility because back mutations are exceedingly rare. Thus, treatment protocols typically are designed to remove or kill cancer cells by surgery, chemotherapy, immunotherapy and/or radiotherapy. However, empirical evidence exists to support a fundamentally different treatment option. For example, the development of experimental cancer in laboratory animals initiated by a powerful mutagen/carcinogen can be repetitively turned on and off by non-mutagenic mechanisms, even completely, by modifying the consumption of protein at relevant levels of intake. Similar but less substantiated evidence also exists for other nutrients and other cancer types. This suggests that cancer is primarily a nutrition-responsive disease rather than a genetic disease, with the understanding that nutrition is defined as a comprehensive, wholistic biological function reflecting the natural composition of nutrients and related substances in whole, intact food.  This function sharply contrasts with the contemporary inference that nutrition is the summation of individual nutrients acting independently. The spelling of ‘holism’ with the ‘w’ is meant to emphasize the empirical basis for this function.  The proposition that nutrition, acting wholistically, controls and even reverses disease development suggests that cancer may be treated by nutritional intervention.

 

Oncology

Angiogenesis and Anti-tumor Immunity in the Tumor Microenvironment: Opportunities for Synergism in Intervention


Author: Christopher Lemmon, Ibrahim Sadek, Zhonglin Hao

Manuscript ID: JNSCI#17-0623

Abstract:

Success of angiogenesis inhibition has met with resurgence of immunomodulation in treatment of metastatic carcinomas. While each of these is effective in some cases, the response rates are low, and resistance soon emerges to single agent treatment. Will combination of the two improve response rate and duration of response through synergy? In addition to blocking neovascular formation, angiogenesis inhibitors (AI) help deliver more effective cytotoxic T lymphocytes to the tumor by improving vascular perfusion. Recent studies also showed that AI not only increased the efficacy of effector immune element but also decreased the number and function of suppressor immune cells such as T-regulatory cells, myeloid-derived suppressor cells or tumor-associated macrophages. In this review, we focus on AI and their effects on antitumor immunity in the tumor microenvironment and their potentials in boosting the efficacy of immunotherapy. In the clinical arena, trials are at the early stage to gauge the feasibility and preliminary signs of synergy.

 

Neuroscience

Acromegaly: Underdiagnosed in patients with prolactinomas


Author: Ekaterina Manuylova, G Edward Vates, Ismat Shafiq

Manuscript ID: JNSCI#17-0602

Abstract:

Acromegaly is a rare disease with mortality rates 2-3 times higher as compared to the general population. The interval from onset of symptoms to the diagnosis may range from one year to several decades. The disease remains under-diagnosed despite improved diagnostic technologies. It is usually a sporadic disease but can be familial in several genetic syndromes, for example, MEN-1, MacCune-Albright syndrome, Carney complex and familial isolated pituitary adenoma. Prolactin secreting pituitary adenoma has been known to co-secrete growth hormone. Review of the literature suggests that up to 4% of patients with prolactinoma can develop acromegaly. Current literature suggests IGF-1 measurement for all prolactinoma patients at the initial diagnosis. Afterwards, bio-chemical screening is not routinely performed per the guidelines; as a result mild cases of acromegaly can be missed. Therefore, routine screening for GH excess should be considered in patients with prolactinoma diagnosis on a regular basis.

 

Medical Sciences

Vancomycin in the treatment of Primary Sclerosing Cholangitis: A Review


Author: Sukhpreet Singh, Kusum K. Kharbanda

Manuscript ID: JNSCI#17-0419

Abstract:

Primary sclerosing cholangitis (PSC) is a disease of the bile ducts that causes inflammation and destruction of the intra- and/or extra-hepatic bile ducts. It is also a progressive disorder that leads to fibrosis and liver failure and also increases risk of malignancy. PSC is a heterogeneous disease that is often associated with inflammatory bowel disease (IBD), mainly ulcerative colitis (UC). As of now, there is no established medical therapy for PSC and a majority of patients will eventually require liver transplantation. PSC is the fifth leading cause for liver transplantation, but transplantation does not guarantee a cure since there is a 20% chance of disease recurrence in the graft. At present the mainstay of therapy is ursodeoxycholic acid (UDCA) which has largely been studied in various randomised control trials but has failed to alter the long-term outcome and natural course of the disease. Pathogenesis of PSC is still not clearly understood but recent advances in understanding the pathogenesis have paved way for trial of new therapeutic agents. Here in this review article, we present information gathered from published case reports/series and randomised control trials on the relationship between the microbiota and PSC pathogenesis with a purpose of understanding whether vancomycin is a potential effective pharmacotherapy for patients with this disease.

 
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