Photodynamic therapy (PDT) is a promising cancer treatment modality that can selectively target unresectable tumors through optical activation of cytotoxic agents, thus reducing many side effects ...associated with systemic administration of chemotherapeutic drugs. However, limited light penetration into most biological tissues have so far prevented its widespread adoption beyond dermatology and a few other oncological applications in which a fiber optic can be threaded to the desired locations via an endoscopic approach (e.g., bladder). In this paper, we introduce an ultrasonically powered implantable microlight source, μLight, which enables in-situ localized light delivery to deep-seated solid tumors. Ultrasonic powering allows for small receiver form factor (mm-scale) and power transfer deep into the tissue (several centimeters). The implants consist of piezoelectric transducers measuring 2 × 2 × 2 mm
and 2 × 4 × 2 mm
with surface-mounted miniature red and blue LEDs. When energized with 185 mW/cm
of transmitted acoustic power at 720 kHz, μLight can generate 0.048 to 6.5 mW/cm
of optical power (depending on size of the piezoelectric element and light wavelength spectrum). This allows powering multiple receivers to a distance of 10 cm at therapeutic light output levels (a delivery of 20-40 J/cm
light radiation dose in 1-2 hours). In vitro tests show that HeLa cells irradiated with μLights undergo a 70% decrease in average cell viability as compared to the control group. In vivo tests in mice implanted with 4T1-induced tumors (breast cancer) show light delivery capability at therapeutic dose levels. Overall, results indicate implanting multiple µLights and operating them for 1-2 hours can achieve cytotoxicity levels comparable to the clinically reported cases using external light sources.
Abstract
The Miniature X-ray Solar Spectrometer (MinXSS-1) CubeSat observed solar X-rays between 0.5 and 10 keV. A two-temperature, two-emission-measure model is fit to each daily averaged spectrum. ...These daily average temperatures and emission measures are plotted against the corresponding daily solar 10.7 cm radio flux (F10.7) value and a linear correlation is found between each that we call the Schwab Woods Mason (SWM) model. The linear trends show that one can estimate the solar spectrum between 0.5 and 10 keV based on the F10.7 measurement alone. The cooler temperature component of this model represents the quiescent Sun contribution to the spectra and is essentially independent of solar activity, meaning the daily average quiescent Sun is accurately described by a single temperature (1.70 MK) regardless of solar intensity and only the emission measure corresponding to this temperature needs to be adjusted for higher or lower solar intensity. The warmer temperature component is shown to represent active region contributions to the spectra and varies between 5 and 6 MK. The Geostationary Operational Environmental Satellite (GOES) XRS-B data between 1 and 8 Å is used to validate this model and it is found that the ratio between the SWM model irradiance and the GOES XRS-B irradiance is close to unity on average. MinXSS-1 spectra during quiescent solar conditions have very low counts beyond around 3 keV. The SWM model can generate MinXSS-1 or Dual Aperture X-ray Solar Spectrometer spectra at very high spectral resolution and with extended energy ranges to fill in gaps between measurements and extend predictions back to 1947.
Abstract In this study, we present the analysis of six solar flare events that occurred in 2022, using new data from the third-generation Miniature X-Ray Solar Spectrometer, also known as the ...Dual-zone Aperture X-ray Solar Spectrometer (DAXSS). The primary focus of this study is on the flare’s onset phase , which is characterized by elevated soft X-ray emissions even before the flare’s impulsive phase. We analyze the temporal evolution of plasma temperature, emission measure, and elemental abundance factors during the flare onset phase by fitting the DAXSS spectra with the Astrophysical Plasma Emission Code model. The model fitting results indicate that the flaring plasma is already at a high temperature (10–15 MK) during the onset period. The temperature rises during the onset phase, followed by a decrease and subsequent increase during the impulsive phase. Elemental abundance factors show a trend of falling below preflare values during the onset phase, with some recovery before the impulsive phase. During the impulsive phase, the abundance factors decrease from elevated coronal values to about photospheric values. We also analyze images from the 193 Å channel of the Atmospheric Imaging Assembly (AIA), highlighting the formation or brightening of coronal loop structures during the onset phase. Two distinct onset loop configurations are observed, which are referred to as one-loop and two-loop onsets. Both DAXSS and AIA observations indicate that the flare onset phase exhibits hot coronal plasma properties similar to those of the impulsive phase, suggesting that the onset phase may act as a preconditioning effect for some flares.
Polo-like kinase 1 (Plk1), a crucial regulator of cell-cycle progression, is overexpressed in multiple types of cancers and has been proven to be a potent and promising target for cancer treatment. ...In case of prostate cancer, we once showed that antineoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the β-catenin pathway and increased expression of c-MYC, eventually resulting in resistance to Plk1 inhibition. JQ1, a selective small-molecule inhibitor targeting the amino-terminal bromodomains of BRD4, has been shown to dramatically inhibit c-MYC expression and AR signaling, exhibiting antiproliferative effects in a range of cancers. Because c-MYC and AR signaling are essential for prostate cancer initiation and progression, we aim to test whether targeting Plk1 and BRD4 at the same time is an effective approach to treat prostate cancer. Herein, we show that a combination of Plk1 inhibitor GSK461364A and BRD4 inhibitor JQ1 had a strong synergistic effect on castration-resistant prostate cancer (CRPC) cell lines, as well as in CRPC xenograft tumors. Mechanistically, the synergistic effect is likely due to two reasons: (i) Plk1 inhibition results in the accumulation of β-catenin in the nucleus, thus elevation of c-MYC expression, whereas JQ1 treatment directly suppresses c-MYC transcription; (ii) Plk1 and BRD4 dual inhibition acts synergistically in inhibition of AR signaling.
.
A stress adaptation pathway termed the integrated stress response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that the eIF2 kinase GCN2 is ...required for sustained growth in androgen-sensitive and castration-resistant models of PCa both in vitro and in vivo, and is active in PCa patient samples. Using RNA-seq transcriptome analysis and a CRISPR-based phenotypic screen, GCN2 was shown to regulate expression of over 60 solute-carrier (
) genes, including those involved in amino acid transport and loss of GCN2 function reduces amino acid import and levels. Addition of essential amino acids or expression of 4F2 (SLC3A2) partially restored growth following loss of GCN2, suggesting that GCN2 targeting of SLC transporters is required for amino acid homeostasis needed to sustain tumor growth. A small molecule inhibitor of GCN2 showed robust in vivo efficacy in androgen-sensitive and castration-resistant mouse models of PCa, supporting its therapeutic potential for the treatment of PCa.
In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is ...unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort (n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort (n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2, exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis.
We present the first performance results obtained with microwave multiplexed Transition Edge Sensors prototypes specifically designed for the HOLMES experiment, a project aimed at directly measuring ...the electron neutrino mass through the calorimetric measurement of the
163
Ho electron capture spectrum. The detectors required for such an experiment feature a high energy resolution at the
Q
–value of the transition, around
∼
2.8 keV, and a fast response time combined with the compatibility to be multiplexed in large arrays in order to collect a large statistics while keeping the pile-up contribution as small as possible. In addition, the design has to be suitable for future ion-implantation of
163
Ho. The results obtained in these tests allowed us to identify the optimal detector design among several prototypes. The chosen detector achieved an energy resolution of (4.5 ± 0.3) eV on the chlorine K
α
line, at
∼
2.6 keV, obtained with an exponential rise time of 14
μ
s. The achievements described in this paper pose a milestone for the HOLMES detectors, setting a baseline for the subsequent developments, aiming to the actual ion-implantation of the
163
Ho nuclei. In the first section the HOLMES experiment is outlined along with its physics goal, while in the second section the HOLMES detectors are described; the experimental set-up and the calibration source used for the measurements described in this paper are reported in Sects.
3
and
4
, respectively; finally, the details of the data analysis and the results obtained are reported in Sect.
6
.
Racehorse training and racing schedules in many parts of the United States and Canada were interrupted or otherwise reduced during the first three to six months of 2020. This was an indirect ...consequence of mitigations to prevent the spread of the pandemic virus COVID-19. Data from the Equine Injury Database, a census-level survey of all race starts made in the USA and Canada, were used to analyse the incidence of fatalities in 2009–2022 among three age cohorts of racehorses within each year. There was a statistically significant increase in the incidence of musculoskeletal fatalities among 2-year-old Thoroughbreds in 2020, compared to the period 2009–2019. In 2021 and 2022, the training schedules of 2-year-old horses returned to pre-2020 levels, as did the incidence of fatalities. The delayed start to training for 2-year-old horses was associated with an increase in risk of fatal musculoskeletal injury for those horses during 2020, but the risk for the same horses in 2021—when they were 3 years old—was not significantly different to the risk for 3-year-olds in any other year. The increased risk of fatal musculoskeletal injury in 2020 was only found among horses that were 2 years old in 2020—horses aged 3 years or more in 2020 were not at increased risk.
Abstract
The Dual-zone Aperture X-ray Solar Spectrometer (DAXSS) was flown on 2018 June 18 on the NASA 36.336 sounding rocket flight and obtained the highest resolution to date for solar soft X-ray ...(SXR) spectra over a broad energy range. This observation was during a time with quiescent (nonflaring) small active regions on the solar disk and when the 10.7 cm radio flux (F10.7) was 75 solar flux units (1 sfu = 10–22 W m
−2
Hz
−1
). The DAXSS instrument consists of a LASP-developed dual-zone aperture and a commercial X-ray spectrometer from Amptek that measures solar full-disk irradiance from 0.5 to 20 keV with a resolving power of 20 near 1 keV. This paper discusses the novel design of the spectrometer and the instrument characterization techniques. Additionally, the solar measurements obtained from the 2018 sounding rocket flight are analyzed using CHIANTI spectral models to fit the temperatures, emission measures, and relative elemental abundances of the solar corona plasma. The abundance of iron was found to be 35% higher than expected in the quiescent Sun’s corona suggesting either that our spectral models require additional sophistication or that the underlying atomic database may require updates. Future long-term systematic observations of this spectral range are needed to provide further insight into the sources of coronal heating through modeling the changes of relative elemental abundances during developments of active regions and solar flaring events.
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