Signaling Networks that Induce Melanomagenesis and Metastasis that can be Exploited for Therapeutic Benefit

Melanoma is the most lethal type of skin cancer and originates in melanocytes, cells that produce the pigment melanin. Five year survival rates are particularly high for this type of cancer if the tumor is diagnosed and treated early. However, survival rates decline significantly if the tumor is allowed to metastasize. Frequency of melanoma has risen over recent years, especially in young people. Much progress has been made in treating melanoma; however, tumor recurrence is frequently seen in patients after treatment has concluded. The leading genes that are found to be mutated in melanoma are v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), phosphatase and tensin homolog deleted on chromosome ten (PTEN) and cyclin dependent kinase inhibitor 2A (CDKN2A) which belong to the MAPK (Mitogen-activated protein kinase/Extracellular signal-regulated kinases) pathway, the phosphoinositide 3\u27 kinase (PI3K)/AKT pathway or the INK4/ARF locus. Together, these two pathways and locus form a signaling network that work in tandem to promote cell proliferation, migration, invasion and metastasis. Recent breakthroughs in treating melanoma include the advent of BRAF inhibitors, but patients often experience tumor recurrence. Research conducted to understand acquired BRAF inhibitor resistance suggests that tumor regrowth is due to continued activation of the MAPK and PI3K/AKT pathways through BRAF independent routes. Therefore, new treatments, which can be personalized, are being developed that target multiple components of both of these pathways. The epigenetic causes of melanoma are vast and are just recently becoming clear

Symbolic integration of a product of two spherical bessel functions with an additional exponential and polynomial factor

We present a mathematica package that performs the symbolic calculation of integrals of the form \int^{\infty}_0 e^{-x/u} x^n j_{\nu} (x) j_{\mu} (x) dx where $j_{\nu} (x)$ and $j_{\mu} (x)$ denote spherical Bessel functions of integer orders, with $\nu \ge 0$ and $\mu \ge 0$. With the real parameter $u>0$ and the integer $n$, convergence of the integral requires that $n+\nu +\mu \ge 0$. The package provides analytical result for the integral in its most simplified form. The novel symbolic method employed enables the calculation of a large number of integrals of the above form in a fraction of the time required for conventional numerical and Mathematica based brute-force methods. We test the accuracy of such analytical expressions by comparing the results with their numerical counterparts.Comment: 17 pages; updated references for the introductio

Simulation of an optically induced asymmetric deformation of a liquid-liquid interface

Deformations of liquid interfaces by the optical radiation pressure of a focused laser wave were generally expected to display similar behavior, whatever the direction of propagation of the incident beam. Recent experiments showed that the invariance of interface deformations with respect to the direction of propagation of the incident wave is broken at high laser intensities. In the case of a beam propagating from the liquid of smaller refractive index to that of larger one, the interface remains stable, forming a nipple-like shape, while for the opposite direction of propagation, an instability occurs, leading to a long needle-like deformation emitting micro-droplets. While an analytical model successfully predicts the equilibrium shape of weakly deformed interface, very few work has been accomplished in the regime of large interface deformations. In this work, we use the Boundary Integral Element Method (BIEM) to compute the evolution of the shape of a fluid-fluid interface under the effect of a continuous laser wave, and we compare our numerical simulations to experimental data in the regime of large deformations for both upward and downward beam propagation. We confirm the invariance breakdown observed experimentally and find good agreement between predicted and experimental interface hump heights below the instability threshold

Cohesinopathies of a feather flock together.

Roberts Syndrome (RBS) and Cornelia de Lange Syndrome (CdLS) are severe developmental maladies that present with nearly an identical suite of multi-spectrum birth defects. Not surprisingly, RBS and CdLS arise from mutations within a single pathway--here involving cohesion. Sister chromatid tethering reactions that comprise cohesion are required for high fidelity chromosome segregation, but cohesin tethers also regulate gene transcription, promote DNA repair, and impact DNA replication. Currently, RBS is thought to arise from elevated levels of apoptosis, mitotic failure, and limited progenitor cell proliferation, while CdLS is thought to arise, instead, from transcription dysregulation. Here, we review new information that implicates RBS gene mutations in altered transcription profiles. We propose that cohesin-dependent transcription dysregulation may extend to other developmental maladies; the diagnoses of which are complicated through multi-functional proteins that manifest a sliding scale of diverse and severe phenotypes. We further review evidence that cohesinopathies are more common than currently posited

Developmental and cytological phenotypes of cohesinopathies and potentially related maladies.

<p>Partial list of developmental and cytological effects in response to cohesion pathway mutations.</p>*<p>Craniofacial dysmorphia include micrognathia, ear abnormalities, wide-set eyes, beaked or prominent nose, arched eyebrows, or low-set ears.</p>+<p>Limb reductions are often symmetric and involve all four limbs in RBS but predominant in upper extremities in CdLS. Limb reduction appears limited to the radius in NBS and FA.</p>**<p>Organ abnormalities may include renal, urinary, gonadal, gastroesophageal, and others.</p>++<p>Detection of cryptic HR/PCS may require cell exposure to mitomycin. ND (Not Diagnostic): most studies document that HR/PCS is not elevated in CdLS cells <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Revenkova1" target="_blank">[17]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Castronovo1" target="_blank">[18]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Vrouwe1" target="_blank">[20]</a>, but see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Kaur1" target="_blank">[48]</a>. While HR/PCS is thus not efficacious as a diagnostic tool, numerous chromosomal aberrations are evident in CdLS cells upon exposure to genotoxic agents <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Vrouwe1" target="_blank">[20]</a>, revealing that CdLS cells may be predispositioned to PCS/HR. Bolded text represents examples of historical cytological diagnostic markers (HR/PCS for RBS, Clastogen sensitivity for FA). Phenotypes shown for potentially cohesinopathic-related developmental maladies (Ribosomopathies TCS and DBA, Nijmegen Breakage Disease, Fanconi Anemia—last four columns) that we speculate are similarly predicated on transcriptional dysregulation <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Vega1" target="_blank">[1]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Schule1" target="_blank">[2]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Musio1" target="_blank">[5]</a>–<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Krantz1" target="_blank">[8]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Morita1" target="_blank">[14]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Liu1" target="_blank">[26]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Gimigliano1" target="_blank">[33]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Leem1" target="_blank">[41]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Kaur1" target="_blank">[48]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-vanderLelij1" target="_blank">[55]</a>–<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-CapoChichi1" target="_blank">[57]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-vanderLelij3" target="_blank">[61]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Kee1" target="_blank">[63]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Auerbach1" target="_blank">[78]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Genetics1" target="_blank">[79]</a>.</p