Interacting Genetic Lesions of Melanoma in the Tumor Microenvironment: Defining a Viable Therapy.

Melanoma is the most aggressive form of skin cancer with an estimated 106,110 newly diagnosed cases in the United States of America in 2021 leading to an approximated 7180 melanoma-induced deaths. Cancer typically arises from an accumulation of somatic mutations and can be associated with mutagenic or carcinogenic exposure. A key characteristic of melanoma is the extensive somatic mutation rate of 16.8 mutations/Mb, which is largely attributed to UV exposure. Bearing the highest mutational load, many of them occur in key driver pathways, most commonly the BRAFV600E in the mitogen-activated protein kinase (MAPK) pathway. This driver mutation is targeted clinically with FDA-approved therapies using small molecule inhibitors of oncogenic BRAFV600E and MEK, which has greatly expanded therapeutic intervention following a melanoma diagnosis. Up until 2011, therapeutic options for metastatic melanoma were limited, and treatment typically fell under the spectrum of surgery, radiotherapy, and chemotherapy.Attributed to the extensive mutation rate, as well as having the highest number of neoepitopes, melanoma is deemed to be extremely immunogenic. However, despite this highly immunogenic nature, melanoma is notorious for inducing an immunosuppressive microenvironment which can be relieved by checkpoint inhibitor therapy. The two molecules currently approved clinically are ipilimumab and nivolumab, which target the molecules CTLA-4 and PD-1, respectively.A plethora of immunomodulatory molecules exist, many with redundant functions. Additionally, these molecules are expressed not only by immune cells but also by tumor cells within the tumor microenvironment. Tumor profiling of these cell surface checkpoint molecules is necessary to optimize a clinical response. The presence of immunomodulatory molecules in melanoma, using data from The Cancer Genome Atlas and validation of expression in two model systems, human melanoma tissues and patient-derived melanoma cells, revealed that the expression levels of B and T lymphocyte attenuator (BTLA), TIM1, and CD226, concurrently with the BRAFV600E mutation status, significantly dictated overall survival in melanoma patients. These molecules, along with herpesvirus entry mediator (HVEM) and CD160, two molecules that are a part of the HVEM/BTLA/CD160 axis, had a higher expression in human melanoma tissues when compared to normal skin melanocytes and have unique roles to play in T cell activation. New links are being uncovered between the expression of immunomodulatory molecules and the BRAFV600E genetic lesion in melanoma. Small molecule inhibitors of the MAPK pathway regulate the surface expression of this multifaceted molecule, making BTLA a promising target for immuno-oncology to be targeted in combination with small molecule inhibitors, potentially alleviating T regulatory cell activation and improving patient prognosis.

Design and operation of a fast electromagnetic inductive massive gas injection valve for NSTX-U.

Results from the operation of an electromagnetic valve, that does not incorporate ferromagnetic materials, are presented. Image currents induced on a conducting disc placed near a pancake solenoid cause it to move away from the solenoid and open the vacuum seal. A new and important design feature is the use of Lip Seals for the sliding piston. The pressure rise in the test chamber is measured directly using a fast time response Baratron gauge. The valve injects over 200 Torr l of nitrogen in less than 3 ms, which remains unchanged at moderate magnetic fields.

Evidence for separatrix formation and sustainment with steady inductive helicity injection.

The first sustainment of toroidal plasma current of 50 kA at up to 3 times the injected currents, added in quadrature, using steady inductive helicity injection is described. Separatrix currents-currents not linking the helicity injectors-are sustained up to 40 kA. Decreases in the n=1 toroidal mode of the poloidal magnetic field at higher current amplifications indicate more quiescent, direct toroidal current drive. Results are achieved in HIT-SI (with a spheromak of major radius 0.3 m) during deuterium operations immediately after helium operation. These results represent a breakthrough in the development of this new current drive method for magnetic confinement fusion.

Demonstration of Tokamak ohmic flux saving by transient coaxial helicity injection in the national spherical torus experiment.

Transient coaxial helicity injection (CHI) started discharges in the National Spherical Torus Experiment (NSTX) have attained peak currents up to 300 kA and when coupled to induction, it has produced up to 200 kA additional current over inductive-only operation. CHI in NSTX has shown to be energetically quite efficient, producing a plasma current of about 10 A/J of capacitor bank energy. In addition, for the first time, the CHI-produced toroidal current that couples to induction continues to increase with the energy supplied by the CHI power supply at otherwise similar values of the injector flux, indicating the potential for substantial current generation capability by CHI in NSTX and in future toroidal devices.

Efficient generation of closed magnetic flux surfaces in a large spherical tokamak using coaxial helicity injection.

A method of coaxial helicity injection has successfully produced a closed flux current without the use of the central solenoid in the NSTX device, on a size scale closer to a spherical torus reactor, for a proof-of-principle demonstration of this concept. For the first time, a remarkable 60 times current multiplication factor was achieved. Grad-Shafranov plasma equilibrium reconstructions are used to verify the existence of closed flux current. In some discharges the generated current persists for a surprisingly long time approximately 400 ms.

Spheromak formation by steady inductive helicity injection.

A spheromak is formed for the first time using a new steady state inductive helicity injection method. Using two inductive injectors with odd symmetry and oscillating at 5.8 kHz, a steady state spheromak with even symmetry is formed and sustained through nonlinear relaxation. A spheromak with about 13 kA of toroidal current is formed and sustained using about 3 MW of power. This is a much lower power threshold for spheromak production than required for electrode-based helicity injection. Internal magnetic probe data, including oscillations driven by the injectors, agree with the plasma being in the Taylor state. The agreement is remarkable considering the only fitting parameter is the amplitude of the spheromak component of the state.

Demonstration of plasma startup by coaxial helicity injection.

The first successful results on the transfer of a coaxial helicity injection (CHI) produced discharge to inductive operation are reported. CHI-assisted plasma startup is more robust than inductive only operation. After hand off for inductive operation, the initial 90 kA of CHI-produced current drops to 40 kA, then ramps up to 170 kA, using only 30 mV s, more than 30% higher than that produced by induction alone. These significant performance enhancing results were obtained on the HIT-II spherical torus experiment (major/minor radius of 0.3/0.2 m).