An extremely rare case of concurrent BRAF V600E mutation driven hairy cell leukemia and melanoma: case report and review of literature

BRAF protein is a serine/threonine kinase with 766 amino acids. Approximately 15% of human cancers harbor BRAF mutations as well as other BRAF anomalies (amplifications, fusions). Somatic mutations mainly occur in the catalytic kinase domain (CR3), and the predominant mutation is p.V600E which is the substitution of glutamic acid (E) for valine (V) as result of a mutation at codon 600 of the kinase domain. To our knowledge, the vast majority of the cancers have non-germline BRAF mutations. Here we describe a case of a 60-year-old female with a history of hairy cell leukemia (HCL) who presented with aphasia and forgetfulness. A follow-up Brain CT scan showed three distinct brain lesions which were found to be diagnostic of melanoma (confirmed by immunohistochemistry) with no evidence of a concurrent brain involvement by a B-cell neoplasm. Molecular studies confirmed the same BRAF p.V600E mutation in both malignancies (hairy cell leukemia and melanoma). Thereafter the patient was started on BRAF inhibitor treatment and is now symptom-free after one year of follow up. Having two concurrent malignancies with a shared BRAF mutation is extremely rare and makes this an excellent example of a genomic marker-driven treatment in two histologically and immunophenotypically distinct tumor

An extremely rare case of concurrent BRAF V600E mutation driven hairy cell leukemia and melanoma: case report and review of literature

BRAF protein is a serine/threonine kinase with 766 amino acids. Approximately 15% of human cancers harbor BRAF mutations as well as other BRAF anomalies (amplifications, fusions). Somatic mutations mainly occur in the catalytic kinase domain (CR3), and the predominant mutation is p.V600E which is the substitution of glutamic acid (E) for valine (V) as result of a mutation at codon 600 of the kinase domain. To our knowledge, the vast majority of the cancers have non-germline BRAF mutations. Here we describe a case of a 60-year-old female with a history of hairy cell leukemia (HCL) who presented with aphasia and forgetfulness. A follow-up Brain CT scan showed three distinct brain lesions which were found to be diagnostic of melanoma (confirmed by immunohistochemistry) with no evidence of a concurrent brain involvement by a B-cell neoplasm. Molecular studies confirmed the same BRAF p.V600E mutation in both malignancies (hairy cell leukemia and melanoma). Thereafter the patient was started on BRAF inhibitor treatment and is now symptom-free after one year of follow up. Having two concurrent malignancies with a shared BRAF mutation is extremely rare and makes this an excellent example of a genomic marker-driven treatment in two histologically and immunophenotypically distinct tumor

Characterization of In Vivo Keratin 19 Phosphorylation on Tyrosine-391

Keratin polypeptide 19 (K19) is a type I intermediate filament protein that is expressed in stratified and simple-type epithelia. Although K19 is known to be phosphorylated on tyrosine residue(s), conclusive site-specific characterization of these residue(s) and identification potential kinases that may be involved has not been reported.In this study, biochemical, molecular and immunological approaches were undertaken in order to identify and characterize K19 tyrosine phosphorylation. Upon treatment with pervanadate, a tyrosine phosphatase inhibitor, human K19 (hK19) was phosphorylated on tyrosine 391, located in the 'tail' domain of the protein. K19 Y391 phosphorylation was confirmed using site-directed mutagenesis and cell transfection coupled with the generation of a K19 phospho (p)-Y391-specific rabbit antibody. The antibody also recognized mouse phospho-K19 (K19 pY394). This tyrosine residue is not phosphorylated under basal conditions, but becomes phosphorylated in the presence of Src kinase in vitro and in cells expressing constitutively-active Src. Pervanadate treatment in vivo resulted in phosphorylation of K19 Y394 and Y391 in colonic epithelial cells of non-transgenic mice and hK19-overexpressing mice, respectively.Human K19 tyrosine 391 is phosphorylated, potentially by Src kinase, and is the first well-defined tyrosine phosphorylation site of any keratin protein. The lack of detection of K19 pY391 in the absence of tyrosine phosphatase inhibition suggests that its phosphorylation is highly dynamic

Discovering the highest energy neutrinos with the Payload for Ultrahigh Energy Observations (PUEO)

The Payload for Ultrahigh Energy Observations (PUEO) is a NASA Long-Duration Balloon Mission that has been selected for concept development. PUEO has unprecedented sensitivity to ultra-high energy neutrinos above 1018 eV. PUEO will be sensitive to both Askaryan emission from neutrino-induced cascades in Antarctic ice and geomagnetic emission from upward-going air showers that are a result of tau neutrino interactions. PUEO is also especially well-suited for point source and transient searches. Compared to its predecessor ANITA, PUEO achieves better than an order-of-magnitude improvement in sensitivity and lowers the energy threshold for detection, by implementing a coherent phased array trigger, adding more channels, optimizing the detection bandwidth, and implementing real-time filtering. Here we discuss the science reach and plans for PUEO, leading up to a 2024 launch

The Payload for Ultrahigh Energy Observations (PUEO): a white paper

The Payload for Ultrahigh Energy Observations (PUEO) long-duration balloon experiment is designed to have world-leading sensitivity to ultrahigh-energy neutrinos at energies above 1 EeV. Probing this energy region is essential for understanding the extreme-energy universe at all distance scales. PUEO leverages experience from and supersedes the successful Antarctic Impulsive Transient Antenna (ANITA) program, with an improved design that drastically improves sensitivity by more than an order of magnitude at energies below 30 EeV. PUEO will either make the first significant detection of or set the best limits on ultrahigh-energy neutrino fluxes

The Payload for Ultrahigh Energy Observations (PUEO): A White Paper

The Payload for Ultrahigh Energy Observations (PUEO) long-duration balloon experiment is designed to have world-leading sensitivity to ultrahigh-energy neutrinos at energies above 1 EeV. Probing this energy region is essential for understanding the extreme-energy universe at all distance scales. PUEO leverages experience from and supersedes the successful Antarctic Impulsive Transient Antenna (ANITA) program, with an improved design that drastically improves sensitivity by more than an order of magnitude at energies below 30 EeV. PUEO will either make the first significant detection of or set the best limits on ultrahigh-energy neutrino fluxes.Comment: 37 pages, 17 figures. Minor updates, version submitted to JINS

Low-threshold ultrahigh-energy neutrino search with the Askaryan Radio Array

In the pursuit of the measurement of the still-elusive ultrahigh-energy (UHE) neutrino flux at energies of order EeV, detectors using the in-ice Askaryan radio technique have increasingly targeted lower trigger thresholds. This has led to improved trigger-level sensitivity to UHE neutrinos. Working with data collected by the Askaryan Radio Array (ARA), we search for neutrino candidates at the lowest threshold achieved to date, leading to improved analysis-level sensitivities. A neutrino search on a data set with 208.7 days of livetime from the reduced-threshold fifth ARA station is performed, achieving a 68% analysis efficiency over all energies on a simulated mixed-composition neutrino flux with an expected background of 0.10-0.04+0.06 events passing the analysis. We observe one event passing our analysis and proceed to set a neutrino flux limit using a Feldman-Cousins construction. We show that the improved trigger-level sensitivity can be carried through an analysis, motivating the phased array triggering technique for use in future radio-detection experiments. We also include a projection using all available data from this detector. Finally, we find that future analyses will benefit from studies of events near the surface to fully understand the background expected for a large-scale detector

The Calibration of the Geometry and Antenna delay in Askaryan Radio Array Station 4 and 5

The Askaryan Radio Array (ARA) experiment at the South Pole is designed to detect the radio signals produced by ultra high energy cosmic neutrino interactions in the ice. There are 5 independent ARA stations, one of which (A5) includes a low-threshold phased array trigger string. Each ARA station is designed to work as an autonomous detector. The Data Acquisition System in all ARA stations is equipped with the Ice Ray Sampler second-generation (IRS2) chip, a custom-made, application-specific integrated circuit (ASIC) for high-speed sampling and digitization. In this contribution, we describe the methodology used to calibrate the IRS2 digitizer chip and the station geometry, namely the relative timing between each pair of ARA antennas, deployed at 200 m below the Antarctic ice surface, and their geometrical positions in the ice, for ARA stations 4 and 5. Our calibration allows for proper timing correlations between incoming signals, which is crucial for radio vertex reconstruction and thus detection of ultra high energy neutrinos through the Askaryan effect. We achieve a signal timing precision on a sub-nanosecond level and an antenna position precision within 10 cm

Implementing a Low-Threshold Analysis with the Askaryan Radio Array (ARA)

The Askaryan Radio Array (ARA) is a ground-based radio detector at the South Pole designed to capture Askaryan emission from ultra-high energy neutrinos interacting within the Antarctic ice. The newest ARA station has been equipped with a phased array trigger, in which radio signals in multiple antennas are summed in predetermined directions prior to the trigger. In this way, impulsive signals add coherently, while noise likely does not, allowing the trigger threshold to be lower than a traditional ARA station. Early results on just a fraction of available data from this new system prove the feasibility of a low-threshold analysis