BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and Resistance

Since the initial discovery that a subset of patients with cutaneous melanoma harbor BRAF mutations, substantial research has been focused on determining the pathologic consequences of BRAF mutations, optimizing diagnostic techniques to identify these mutations, and developing therapeutic interventions to inhibit the function of this target in mutation-bearing tumors. Recently, advances have been made which are revolutionizing the standard of care for patients with BRAF mutant melanoma. This paper provides an overview on the pathogenic ramifications of mutant BRAF signaling, the latest molecular testing methods to detect BRAF mutations, and the most recent clinical data of BRAF pathway inhibitors in patients with melanoma and BRAF mutations. Finally, emerging mechanisms of resistance to BRAF inhibitors and ways of overcoming this resistance are discussed

The Forgotten Numbers: A Closer Look at COVID-19 Non-Fatal Valuations

17 USC 105 interim-entered record; under review.Our research estimates COVID-19 non-fatal economic losses in the U.S. using detailed data on cumulative cases and hospitalizations from January 22, 2020 to July 27, 2020, from the Centers for Disease Control and Prevention (CDC). As of July 27, 2020, the cumulative confirmed number of cases was about 4.2 million with almost 300,000 of them entailing hospitalizations. Due to data collection limitations the confirmed totals reported by the CDC undercount the actual number of cases and hospitalizations in the U.S. Using standard assumptions provided by the CDC, we estimate that as of July 27, 2020, the actual number of cumulative COVID-19 cases in the U.S. is about 47 million with almost 1 million involving hospitalizations. Applying value per statistical life (VSL) and relative severity/injury estimates from the Department of Transportation (DOT), we estimate an overall non-fatal unadjusted valuation of $2.2 trillion for the U.S. with a weighted average value of about$46,000 per case. This is almost 40% higher than the total valuation of $1.6 trillion (using about$11 million VSL from the DOT) for all approximately 147,000 COVID-19 fatalities. We also show a variety of estimates that adjust the non-fatal valuations by the dreaded and uncertainty aspect of COVID-19, age, income, and a factor related to fatality categorization. The adjustments show current overall non-fatal valuations ranging from about $1.5 trillion to about$9.6 trillion. Finally, we use CDC forecast data to estimate non-fatal valuations through November 2020, and find that the overall cumulative valuation increases from about $2.2 trillion to about$5.7 trillion or to about 30% of GDP. Because of the larger numbers of cases involved our calculations imply that non-fatal infections are as economically serious in the aggregate as ultimately fatal infections.Identified in text as U.S. Government work

Genetic Approach to Elucidate the Role of Cyclophilin D in Traumatic Brain Injury Pathology

Cyclophilin D (CypD) has been shown to play a critical role in mitochondrial permeability transition pore (mPTP) opening and the subsequent cell death cascade. Studies consistently demonstrate that mitochondrial dysfunction, including mitochondrial calcium overload and mPTP opening, is essential to the pathobiology of cell death after a traumatic brain injury (TBI). CypD inhibitors, such as cyclosporin A (CsA) or NIM811, administered following TBI, are neuroprotective and quell neurological deficits. However, some pharmacological inhibitors of CypD have multiple biological targets and, as such, do not directly implicate a role for CypD in arbitrating cell death after TBI. Here, we reviewed the current understanding of the role CypD plays in TBI pathobiology. Further, we directly assessed the role of CypD in mediating cell death following TBI by utilizing mice lacking the CypD encoding gene Ppif. Following controlled cortical impact (CCI), the genetic knockout of CypD protected acute mitochondrial bioenergetics at 6 h post-injury and reduced subacute cortical tissue and hippocampal cell loss at 18 d post-injury. The administration of CsA following experimental TBI in Ppif-/- mice improved cortical tissue sparing, highlighting the multiple cellular targets of CsA in the mitigation of TBI pathology. The loss of CypD appeared to desensitize the mitochondrial response to calcium burden induced by TBI; this maintenance of mitochondrial function underlies the observed neuroprotective effect of the CypD knockout. These studies highlight the importance of maintaining mitochondrial homeostasis after injury and validate CypD as a therapeutic target for TBI. Further, these results solidify the beneficial effects of CsA treatment following TBI

Heterogeneous ice nucleation properties of natural desert dust particles coated with a surrogate of secondary organic aerosol

Ice nucleation abilities of surface collected mineral dust particles from the Sahara (SD) and Asia (AD) are investigated for the temperature (T) range 253–233 K and for supersaturated relative humidity (RH) conditions in the immersion freezing regime. The dust particles were also coated with a proxy of secondary organic aerosol (SOA) from the dark ozonolysis of α-pinene to better understand the influence of atmospheric coatings on the immersion freezing ability of mineral dust particles. The measurements are conducted on polydisperse particles in the size range 0.01–3 µm with three different ice nucleation chambers. Two of the chambers follow the continuous flow diffusion chamber (CFDC) principle (Portable Ice Nucleation Chamber, PINC) and the Colorado State University CFDC (CSU-CFDC), whereas the third was the Aerosol Interactions and Dynamics in the Atmosphere (AIDA) cloud expansion chamber. From observed activated fractions (AFs) and ice nucleation active site (INAS) densities, it is concluded within experimental uncertainties that there is no significant difference between the ice nucleation ability of the particular SD and AD samples examined. A small bias towards higher INAS densities for uncoated versus SOA-coated dusts is found but this is well within the 1σ (66 % prediction bands) region of the average fit to the data, which captures 75 % of the INAS densities observed in this study. Furthermore, no systematic differences are observed between SOA-coated and uncoated dusts in both SD and AD cases, regardless of coating thickness (3–60 nm). The results suggest that any differences observed are within the uncertainty of the measurements or differences in cloud chamber parameters such as size fraction of particles sampled, and residence time, as well as assumptions in using INAS densities to compare polydisperse aerosol measurements which may show variable composition with particle size. Coatings with similar properties to that of the SOA in this work and with coating thickness up to 60 nm are not expected to impede or enhance the immersion mode ice nucleation ability of mineral dust particles.ISSN:1680-7375ISSN:1680-736

SWI/SNF-like chromatin remodeling factor Fun30 supports point centromere function in S. cerevisiae

Budding yeast centromeres are sequence-defined point centromeres and are, unlike in many other organisms, not embedded in heterochromatin. Here we show that Fun30, a poorly understood SWI/SNF-like chromatin remodeling factor conserved in humans, promotes point centromere function through the formation of correct chromatin architecture at centromeres. Our determination of the genome-wide binding and nucleosome positioning properties of Fun30 shows that this enzyme is consistently enriched over centromeres and that a majority of CENs show Fun30-dependent changes in flanking nucleosome position and/or CEN core micrococcal nuclease accessibility. Fun30 deletion leads to defects in histone variant Htz1 occupancy genome-wide, including at and around most centromeres. FUN30 genetically interacts with CSE4, coding for the centromere-specific variant of histone H3, and counteracts the detrimental effect of transcription through centromeres on chromosome segregation and suppresses transcriptional noise over centromere CEN3. Previous work has shown a requirement for fission yeast and mammalian homologs of Fun30 in heterochromatin assembly. As centromeres in budding yeast are not embedded in heterochromatin, our findings indicate a direct role of Fun30 in centromere chromatin by promoting correct chromatin architecture

Laser Applications

Contains research objectives and reports on three research projects.Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DAAB07-71-C-0300U. S. Air Force Office of Scientific Research (Contract F44620-71-C-0051)Naval Air Systems Comman

HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease.

Kaposi sarcoma-associated herpesvirus infection is associated with the development of 3 proliferative diseases: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. These conditions are also intimately associated with human immunodeficiency virus infection, and important synergistic interactions between these 2 viruses have been described. Despite differences in viral gene expression patterns in each condition, Kaposi sarcoma-associated herpesvirus encodes similar oncogenic proteins that promote the activation of sequential and parallel signaling pathways. Therapeutic strategies have been implemented to target these unique signaling pathways, and this sort of molecular targeting is the focus of many current research efforts. The scope of this review is to present contemporary knowledge about the epidemiology, virology, and immunology of Kaposi sarcoma-associated herpesvirus and to highlight several key oncogene products that may be targets for chemotherapy

Defying the Tone at the Top: An Analysis on the Effects of Board Characteristics on the Level of Tax Avoidance Across Philippine Publicly Listed Firms

Over the years, the growing culture of tax avoidance among multinational companies around the world has shed light on the importance of improving corporate governance mechanisms. In the Philippines, poor tax collection due to tax leakages has contributed to chronic fiscal deficits in the country. The literature argues that good corporate governance mechanisms (e.g., the structure of the board of directors) play a significant role in ensuring that the management acts in the best interest of the firm and shareholders, thus eventually helping to mitigate the incidences of corporate tax avoidance. Specifically, agency theory argues that the presence of more independent- and female-dominated boards lead to lesser corporate tax avoidance because such directors are stricter in monitoring management. On the other hand, the resource dependency theory posits that firms with boards having more independent, older, and business-educated directors are more likely to engage in tax avoidance because such directors have the experience, expertise, and knowhow to engage in tax avoidance strategies. This paper examines the impact of various board characteristics on the incidence of tax avoidance across nonfinancial and publicly-traded Philippine firms during the period 2003 to 2015. We use the residual book-tax gap, the cash-effective tax rate, and the long run effective tax rate to measure corporate tax avoidance, whereas board characteristics include board size, board age, board independence, CEO-Chair duality, gender diversity, and the educational background of directors. We employ the two-step Blundell-Bond System Generalized Method of Moments (GMM) estimation technique to address endogeneity issues that may confound the relationship between board composition and structure and the level of tax avoidance within the firm. Overall, we find no significant relationship between board characteristics and tax avoidance, as measured by the long-run cash effective tax rates. However, consistent with the agency and resource dependency theories, we find that board age is positively related with corporate tax avoidance, as measured by the residual book-tax gap, whereas board independence and the proportion of board members with post-graduate degrees in Business and Economics have a negative and positive relationship, respectively, when corporate tax avoidance is proxied by the cash effective tax rate. These findings suggest that the case for increasing the number of independent directors and reducing the number of older directors in boards of Philippine publicly listed firms may help reduce incidences of corporate tax avoidance