Mitogen-activated protein kinase (MAPK) cascades are key signaling pathways involved in the regulation of normal cell proliferation, survival and differentiation. Aberrant regulation of MAPK cascades contribute to cancer and other human diseases. In particular, the extracellular signal-regulated kinase (ERK) MAPK pathway has been the subject of intense research scrutiny leading to the development of pharmacologic inhibitors for the treatment of cancer. ERK is a downstream component of an evolutionarily conserved signaling module that is activated by the Raf serine/threonine kinases. Raf activates the MAPK/ERK kinase (MEK)1/2 dual-specificity protein kinases, which then activate ERK1/2. The mutational activation of Raf in human cancers supports the important role of this pathway in human oncogenesis. Additionally, the Raf-MEK-ERK pathway is a key downstream effector of the Ras small GTPase, the most frequently mutated oncogene in human cancers. Finally, Ras is a key downstream effector of the epidermal growth factor receptor (EGFR), which is mutationally activated and/or overexpressed in a wide variety of human cancers. ERK activation also promotes upregulated expression of EGFR ligands, promoting an autocrine growth loop critical for tumor growth. Thus, the EGFR-Ras-Raf-MEK-ERK signaling network has been the subject of intense research and pharmaceutical scrutiny to identify novel target-based approaches for cancer treatment. In this review, we summarize the current status of the different approaches and targets that are under evaluation and development for the therapeutic intervention of this key signaling pathway in human disease.

Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.

Writing committee me tions to which their s ply; see Appendix ACCF/AHATask Fo Surgeons Representa tative Heart Rhythm ography and Int Echocardiography Re ciety of America Rep resentative kkACCF/ Task Force member d This document was app Board of Trustees and ordinating Committee gery, American Soc Cardiology, Heart Fa for Cardiovascular A geons approved the d The American Associat as follows: Gersh BJ Naidu SS, Nishimura Bernard J Gersh, MB, ChB, DPhil, FACC, FAHA, Co-Chair* Barry J Maron, MD, FACC, CoChair* Robert O Bonow, MD, MACC, FAHA, Joseph A Dearani, MD, FACC,§,k Michael A Fifer, MD, FACC, FAHA,* Mark S Link, MD, FACC, FHRS,* Srihari S Naidu, MD, FACC, FSCAI,* Rick A Nishimura, MD, FACC, FAHA, Steve R Ommen, MD, FACC, FAHA, Harry Rakowski, MD, FACC, FASE,** Christine E Seidman, MD, FAHA, Jeffrey A Towbin, MD, FACC, FAHA, James E Udelson, MD, FACC, FASNC, and Clyde W Yancy, MD, FACC, FAHAkk

/pdf/2011-accf-aha-guideline-for-the-diagnosis-and-treatment-of-4tvvqpnd44.pdf

2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.

Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents interacting via pathways activated by receptor-dependent and -independent mechanisms, in hormonal, auto-, para-, or intracrine fashion. Because of the multidirectional nature and heterogeneous character of the melanogenesis modifying agents, its controlling factors are not organized into simple linear sequences, but they interphase instead in a multidimensional network, with extensive functional overlapping with connections arranged both in series and in parallel. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortins and ACTH, whereas among the negative regulators agouti protein stands out, determining intensity of melanogenesis and also the type of melanin synthesized. Within the context of the skin as a stress organ, melanogenic activity serves as a unique molecular sensor and transducer of noxious signals and as regulator of local homeostasis. In keeping with these multiple roles, melanogenesis is controlled by a highly structured system, active since early embryogenesis and capable of superselective functional regulation that may reach down to the cellular level represented by single melanocytes. Indeed, the significance of melanogenesis extends beyond the mere assignment of a color trait.

https://www.physiology.org/doi/pdf/10.1152/physrev.00044.2003

Melanin Pigmentation in Mammalian Skin and Its Hormonal Regulation

Ras genes are the most common targets for somatic gain-of-function mutations in human cancer. Recently, germline mutations that affect components of the Ras-Raf- mitogen-activated and extracellular-signal regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway were shown to cause several developmental disorders, including Noonan, Costello and cardio-facio-cutaneous syndromes. Many of these mutant alleles encode proteins with aberrant biochemical and functional properties. Here we will discuss the implications of germline mutations in the Ras-Raf-MEK-ERK pathway for understanding normal developmental processes and cancer pathogenesis.

http://dipbsf.uninsubria.it/monti/BFPN%202010/Biblio%20BFPN%202010/BFPN%20Ras-Raf%20etc/hyperactive%20Ras.pdf

Hyperactive Ras in developmental disorders and cancer.

2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons

Biobanks are bioresources of human samples linked to relevant personal and health data of the participants, which are collected, processed and stored in an organised system. Their primary purpose is to provide biospecimens for researchers to help improve knowledge on human health and diseases, while appropriately protecting the interests, rights and privacy of the participants.



The biobanking community poses a variety of legal, ethical, social and regulatory challenges, particularly involved in genetic diseases, to be overcome because of the sensitive data they store. A crucial avenue for a biobank to build and maintain public trust is therefore through the development of governance mechanisms ensuring that, in pursuing its remit, the biobank acts in compliance with the applicable laws and regulations of the country in which it is located, as well as the international regulations in order to ease the cross-border sample exchange and the international cooperation of biobanks.



Key Concepts 

Biobanks are collections of human samples linked to relevant personal and health data of the participants, organised and managed in a systematic way.
Primary purpose of biobanks is to help improve knowledge on human health and diseases.
Biobanking poses a variety of challenges including ethical, legal and social issues (ELSI).
Because of the preciousness of the samples and the sensitive nature of the data stored in biobanks, proper governance is essential to protecting confidentiality, choices and rights of participants.
As critical components in the field of clinical practice and basic research, biobanks develop standard operating procedures devoted to collect, process, store, retrieve and transfer to researchers a set of biospecimens and associated information.
In the field of rare diseases (RDs), collectively affecting 6–8% of the population, international cooperation among RD-biobanks is fundamental for sharing and achieving a critical mass of samples and data for basic, translational and clinical research.
To ease an international cooperation, biobanks also need to act in compliance with international regulations.




Keywords:

biobanking;
rare genetic diseases;
networking;
harmonisation and standardisation;
ethical, legal and social issues (ELSI);
IT structure;
genetic data;
privacy protection;
governance;
sustainability

Biobanking for Genetic Diseases

The mucopolysaccharidoses (MPSs) are a group of 11 distinct metabolic disorders that result from the deficiency of the various lysosomal enzymes required to degrade the glycosaminoglycans (GAGs) that constitute a major component of the extracellular matrix, joint fluid and connective tissue. The progressive lysosomal accumulation of GAGs ultimately impairs joint mobility and adversely affects the skeleton and cardiovascular system. Depending on the type or subtype of mucopolysaccharidosis, mental development may range from normal to profoundly impaired. Enzymatic and molecular diagnostic testing are available for all the MPSs. Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) are the only specific treatments for MPS currently available.

Mucopolysaccharide Storage Disorders

The connection between ERAD, UPR, Gaucher disease and Parkinson disease

Mannosidosis is a human lysosomal storage disease caused by and acid alpha-mannosidase deficiency. We have studied two affected Italian families and in this paper discuss the problems concerning the clinical and radiological findings, and laboratory assay as an access to diagnosis. Reference is made to our personal experience, as concerns the difficulties of carrier detection and of prenatal diagnosis.

Mannosidosis. Study of two families and prenatal diagnosis

The transfer of genomic information into the primary RNA sequence can be altered by RNA editing. We have previously shown that genomic variants can be RNA-edited to wild-type. The presence of distinct “edited” iduronate 2-sulfatase (IDS) mRNA transcripts ex vivo evidenced the correction of a nonsense and frameshift variant, respectively, in three unrelated Hunter syndrome patients. This phenomenon was confirmed in various patient samples by a variety of techniques, and was quantified by single-nucleotide primer extension. Western blotting also confirmed the presence of IDS protein similar in size to the wild-type. Since preliminary experimental evidence suggested that the “corrected” IDS proteins produced by the patients were similar in molecular weight and net charge to their wild-type counterparts, an in vitro system employing different cell types was established to recapitulate the site-specific editing of IDS RNA (uridine to cytidine conversion and uridine deletion), and to confirm the findings previously observed ex vivo in the three patients. In addition, confocal microscopy and flow cytometry analyses demonstrated the expression and lysosomal localization in HEK293 cells of GFP-labeled proteins translated from edited IDS mRNAs. Confocal high-content analysis of the two patients’ cells expressing wild-type or mutated IDS confirmed lysosomal localization and showed no accumulation in the Golgi or early endosomes.

/pdf/in-vitro-recapitulation-of-the-site-specific-editing-to-wild-2iop7f0ev2.pdf

In vitro recapitulation of the site-specific editing (to wild-type) of mutant IDS mRNA transcripts, and the characterization of IDS protein translated from the edited mRNAs

Mirella Filocamo

Papers

Biobanking for Genetic Diseases

Mucopolysaccharide Storage Disorders

The connection between ERAD, UPR, Gaucher disease and Parkinson disease

Mannosidosis. Study of two families and prenatal diagnosis

In vitro recapitulation of the site-specific editing (to wild-type) of mutant IDS mRNA transcripts, and the characterization of IDS protein translated from the edited mRNAs