Vol 2-6 Research Article

Waardenburg Syndrome Expression and Penetrance

Myeshia V. Shelby*

Department of Genetics and Human Genetics, Howard University Graduate School, Howard University, USA

Through a combination of in silico research and reviews of previous work, mechanisms by which nonsense-mediated mRNA decay (NMD) affects the inheritance and expressivity of Waardenburg syndrome is realized. While expressivity and inheritance both relate to biochemical processes underlying a gene’s function, this research explores how alternative splicing and premature termination codons (PTC’s) within mRNAs mutated in the disease are either translated into deleterious proteins or decayed to minimize expression of altered proteins. Elucidation of splice variants coupled with NMD perpetuating the various symptoms and inheritance patterns of this disease represent novel findings. By investigating nonsense mutations that lie within and outside the NMD boundary of these transcripts we can evaluate the effects of protein truncation versus minimized protein expression on the variable expressivity found between Type I and Type III Waardenburg syndrome, PAX3, while comparatively evaluating EDN3 and SOX10’s role in inheritance of Type IV subtypes of the disease. This review will demonstrate how alternative splicing perpetuates or limits NMD activity by way of PTC positioning, thereby affecting the presentation of Waardenburg syndrome.

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Vol 2-6 Mini Review

Clinical significance of the depth of invasion in superficial Barrett's esophageal adenocarcinoma.

Junya Oguma, Soji Ozawa*, Akihito Kazuno, Miho Nitta, Yamato Ninomiya, Kentaro Yatabe

Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan

Superficial Barrett’s esophageal adenocarcinoma limited to the lamina propria, like other superficial cancers, is associated with almost no risk of lymph node metastasis. However, lymph node metastasis has been observed in patients with Barrett’s esophageal adenocarcinoma invading the muscularis mucosae. The duplication of the muscularis mucosae is a pathological characteristic of Barrett’s esophagus; however, the rate of lymph node metastasis might not differ according to the depth of invasion within the muscularis mucosae. Submucosal invasion is considered to be a risk factor for lymph node metastasis; however, many reports have suggested that submucosal invasion alone is not a risk factor but that the likelihood of lymph node metastasis increases as the number of risk factors increases. Generally, lymphovascular invasion, pathological differentiation and tumor size are also considered to be risk factors for lymph node metastasis. Previous reports have suggested that patients with superficial Barrett’s esophageal adenocarcinoma limited to T1b-SM1 may have a lower risk of lymph node metastasis and might be candidates for endoscopic resection if other risk factors are negative.

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Vol 2-6 Mini Review

Vitamin D deficient rickets: Not always nutritional

Angham Nasser Al Mutair1,2,3, Yasser Ali Binafif1

1Department of Pediatrics, Endocrinology Division, King Abdulaziz Medical City -Riyadh, King Abdullah Specialist Children Hospital (KASCH).
2King Saud bin Abdulaziz University for Health Sciences.
3King Abdullah International Medical Research Center, Riyadh 11155, Kingdom of Saudi Arabia.

Rickets in pediatrics due to vitamin D deficiency is still considering a major problem even in sunny and tropical countries. The prevalence of vitamin D deficiency and insufficiency in children between 6 and 15 years of age in the Kingdom of Saudi Arabia is 95.4%. Vitamin D requires two steps of hydroxylation to be functionally active. The first hydroxylation step occur in the liver by 25-hydroxylase encoded by CYP2R1 gene (11p15.2) to produce 25(OH)D3 and the second step of hydroxylation occur in proximal convoluted tubules in kidney by 1α-hydroxylase encoded by CYP27B1 gene (12q13.1) to produce hormonally active 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3). Vitamin D-dependent rickets type 1B (VDDR1B) is a form of rickets due to mutation in CYP2R1 gene. Until today, only five mutations were found to affect CYP2R1 gene which lead to abnormal structure and function of 25-hydroxylase enzyme. Presence of symptoms of vitamin D deficiency in good dietary history with poor response or depending on regular to high dose of vitamin D2 or D3 to maintain 25(OH)D3 level should raise the suspicion of genetic causes of CYP2R1 mutations. These mutations are inherited as autosomal recessive; the severity and response to medication depend on number of allele affected. Some of the homogenous mutation patients showed some improvement in using Calcitriol. Bypassing the first step of hydroxylation (25-hydroxylase) in liver using 25-OH-D3 (Calcifediol) as treatment lead to dramatic improvement of biochemical and radiological finding in seven recent reported cases which needs further study.

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Vol 2-6 Commentary

Commentary: Characterization and targeting of Platelet-Derived growth factor receptor alpha (PDGFRA) in Inflammatory breast cancer (IBC)

Kenneth L. van Golen*

The laboratory for cytoskeletal physiology, Department of biological sciences, The university of delaware, The center for translational cancer research, The Helen F. Graham Cancer Center, Newark, DE, USA

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Vol 2-6 Mini Review

Mini-review: The role of mast cells in pulmonary hypertension

Yijie Hu1,2, Wolfgang M. Kuebler1,3,4

1Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada
2Department of Cardiovascular Surgery, Institute of Surgical Research, Daping Hospital, Third Military Medical University, Chongqing, China
3Departments of Surgery and Physiology, University of Toronto, Toronto, ON, Canada
4Institute of Physiology, Charité Universitätsmedizin Berlin, Berlin, Germany

Of recent, inflammatory responses, formation of ectopic lymphoid tissue and autoantibodies have been increasingly implicated in the pathophysiology of pulmonary hypertension (PH). One of the earliest immune cells detected in PH and implicated in its pathogenesis were mast cells based on their demonstrated abundance in the vicinity of vascular lesions in PH patients, as well as in lungs of animal models of PH. Experimental studies using mast cell stabilizers or mast cell deficient rats in classic PH models provided proof-of-principle for the functional relevance of mast cells in the initiation and/or progression of PH and lung vascular remodeling. Yet, the cellular mechanisms by which mast cells contribute to the development of PH and pulmonary vascular remodeling has so far remained largely unclear. Importantly, understanding the downstream effectors by which activated mast cells and their secretome trigger or promote vascular remodeling may lead to the development of novel therapies for PH. Notably, recent work has unveiled a novel interplay between mast cells and the adaptive immune system in PH, in that mast cell-targeted interventions attenuate the formation of tertiary lymphoid tissue in the lung and the formation of autoantibodies. This minireview will focus on the role of mast cells in PH and their possible downstream mechanism.

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Vol 2-6 Mini Review

The soluble guanylate cyclase stimulator riociguat: Evidence in pulmonary hypertension and beyond

Raymond Benza1*, Amresh Raina2, Manreet K. Kanwar3, Steven D. Nathan4, Stephen C. Mathai5

1Advanced Heart Failure, Transplant, Mechanical Circulatory Support and Pulmonary Hypertension Section, Allegheny Health Network, Pittsburgh, PA, USA
2Pulmonary Hypertension Program, Allegheny Health Network, Pittsburgh, PA, USA
3Chronic Thromboembolic Pulmonary Hypertension Program, Allegheny Health Network, Pittsburgh, PA, USA
4Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Vienna, VA, USA
5Johns Hopkins University School of Medicine, Division of Pulmonary and Critical Care Medicine, Baltimore, MD, USA

The soluble guanylate cyclase (sGC) stimulators riociguat and vericiguat elevate intracellular cyclic guanosine monophosphate (cGMP) levels via stimulation of the nitric oxide–sGC–cGMP pathway resulting in vasodilatory, anti-inflammatory, anti-proliferative, and anti-fibrotic effects. Riociguat is approved for the treatment of pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). Placebo-controlled phase 3 trials in both indications demonstrated significant improvements in exercise capacity, functional class, and pulmonary hemodynamics, with sustained efficacy and good tolerability in long-term open-label extension studies. Pilot or phase 2 studies of riociguat in pulmonary hypertension associated with heart failure (HF) or chronic obstructive pulmonary disease showed improvements in some hemodynamic parameters, although riociguat is contraindicated in pulmonary hypertension associated with idiopathic interstitial pneumonias. Riociguat is undergoing trials in other conditions including diffuse cutaneous systemic sclerosis. Vericiguat, a novel once-daily sGC stimulator, is well tolerated in patients with HF and is undergoing a phase 3 trial in HF with reduced ejection fraction. These ongoing studies will clarify the roles of sGC stimulators in indications beyond PAH and CTEPH.

6MWD: 6-minute walking distance; cGMP: cyclic guanosine monophosphate; CTEPH: chronic thromboembolic pulmonary hypertension; dcSSc: diffuse cutaneous systemic sclerosis; HF: heart failure; LVEF: left ventricular ejection fraction; mPAP: mean pulmonary artery pressure; NO: nitric oxide; NT-proBNP: N-terminal pro-brain natriuretic peptide; PAH: pulmonary arterial hypertension; PDE5: phosphodiesterase type 5; PEA: pulmonary endarterectomy; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; RP: Raynaud's phenomenon; sGC: soluble guanylate cyclase; tid: three times daily; WHO: World Health Organization.

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Vol 2-6 Mini Review

A mini review on neurofibromatosis type 1 from the radiological point of view

Monika Bekiesinska-Figatowska1*

1Department of Diagnostic Imaging, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland

Neurofibromatosis type one (NF1) belongs to the most frequent rare diseases, requiring various methods of diagnostic imaging at different stages of diagnostics and follow-up. Magnetic resonance imaging (MRI) is a method of choice in diagnostics of brain: unidentified neurofibromatosis objects, optic pathway gliomas and other tumours which can spontaneously regress. NF1 patients suffer from vascular abnormalities with a predominance of aortic, renal, mesenteric, and carotid-vertebral stenoses or aneurysms. These are evaluated by ultrasound, computed tomography- or MRI-angiography and by digital subtraction angiography. In our material we described twofold higher occurrence of arterial variants in brain in NF1 than in the control group. Characteristic skeletal changes include tibial pseudarthrosis, scoliosis, sphenoid wing dysplasia, rib penciling, and gracile bones, usually diagnosed with plain radiographs. Outside CNS we deal with neurofibromas and plexiform neurofibromas in any location in the body. Their malignant transformation leads to development of malignant peripheral nerve sheath tumour, or malignant triton tumour. Rhabdomyosarcoma, juvenile myelomonocytic leukemia and phaeochromocytoma are also encountered in NF1 patients with increased frequency. Regular imaging follow-up studies should not be routinely performed in NF1 patients. MRI is recommended for follow-up of clinically suspected tumours, single whole-body MR is recommended at transition to adulthood. Positron emission tomography/computed tomography is useful for the detection of malignant transformation of tumours in NF1 patients.

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Vol 2-6 Mini Review

Clinical use of ESAs in Low-Risk Myelodysplastic Syndromes

Ambra Di Veroli1, Eleonora De Bellis1, Valentina Rossi1, Annalisa Biagi1, Vito Rapisarda1, Luca Maurillo1, Maria Ilaria Del Principe1, Maria Teresa Voso1, Adriano Venditti1 and Francesco Buccisano1

1Hematology, Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy

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