Systematic identification of a synthetic lethal interaction in brain-metastatic lung adenocarcinoma.

Metastatic lung adenocarcinoma (LuAC) presents a significant clinical challenge due to the short latency and the lack of efficient treatment options. Therefore, identification of molecular vulnerabilities in metastatic LuAC holds great importance in the development of therapeutic drugs against this disease. In this study, we performed a genome-wide siRNA screening using poorly and highly brain-metastatic LuAC cell lines. Using this approach, we discovered that compared to poorly metastatic LuAC (LuAC-Par) cells, brain-metastatic LuAC (LuAC-BrM) cells exhibited a significantly higher vulnerability to c-FLIP (an inhibitor of caspase-8)-depletion-induced apoptosis. Furthermore, in vivo studies demonstrated that c-FLIP knockdown specifically inhibited growth of LuAC-BrM, but not the LuAC-Par, tumors, suggesting the addiction of LuAC-BrM to the function of c-FLIP for their survival. Our in vitro and in vivo analyses also demonstrated that LuAC-BrM is more sensitive to c-FLIP-depletion due to ER stress-induced activation of the c-JUN and subsequent induction of stress genes including ATF4 and DDIT3. Finally, we found that c-JUN not only sensitized LuAC-BrM to c-FLIP-depletion-induced cell death but also promoted brain metastasis in vivo, providing strong evidence for c-JUN's function as a double-edged sword in LuAC-BrM. Collectively, our findings not only reveal a novel link between c-JUN, brain metastasis, and c-FLIP addiction in LuAC-BrM but also present an opportunity for potential therapeutic intervention.

Real-World Safety and Clinical Outcomes of Macitentan in Asian Patients with Pulmonary Arterial Hypertension: A Prospective Multicenter Study.

BACKGROUND AND OBJECTIVE: Macitentan is approved for treating pulmonary arterial hypertension. However, the real-world evidence of macitentan use is limited. Therefore, we evaluated the safety and clinical outcomes of macitentan use in clinical practice under a post-marketing surveillance. METHODS: Patients with pulmonary arterial hypertension receiving macitentan treatment were prospectively and consecutively enrolled from 2014 to 2020 at 50 medical centers in Korea. Safety and clinical outcomes were monitored from baseline to the nearest timepoint of 24 weeks after macitentan initiation. The adverse events and adverse drug reactions were identified. Changes in the World Health Organization functional class were assessed as the primary clinical outcome, which was used to estimate the final effectiveness (both improved and maintained). Factors associated with safety and final effectiveness were identified. RESULTS: Among 474 patients enrolled in the study, 467 and 440 were included in the safety and clinical outcome analyses, respectively. Dyspnea, nasopharyngitis, and worsening pulmonary arterial hypertension were the most frequent adverse events with incidences of 5%, 3%, and 3%, respectively. The final effectiveness rate was 93%. Older age (adjusted odds ratio [aOR] = 1.021, p = 0.003) and higher level (III vs II) of baseline World Health Organization functional class (aOR = 1.784; p = 0.022) were significantly associated with a higher adverse event occurrence. Younger age (aOR = 0.947; p = 0.001) and shorter disease duration (aOR = 0.991; p = 0.010) were significantly associated with positive final effectiveness. CONCLUSIONS: This real-world study demonstrated the safety and clinical outcomes of macitentan use in Korean patients with pulmonary arterial hypertension. Macitentan was well tolerated and significantly effective with no new safety concerns during the 24 weeks.

Method for spot urine normalization by 40K in a radiation emergency.

In this study, to assess the internal radiation dose in radiation emergencies, the variability of spot urine normalization methods is studied using 40K measurement results. The mean creatinine concentration and the mean 40K activity concentration in the spot urine samples studied were 139 mg dL-1 and 106 Bq kg-1, respectively. The results indicate that the 40K activity concentration method can be used to complement the method used for normalizing the creatinine concentration in spot urine in a radiological emergency.

Improving the resilience of SMEs in times of crisis: The impact of mobile money amid Covid-19 in Zambia.

This study investigates the impact of mobile money (MM) on SMEs' resilience and the associated business outcome in developing countries amid Covid-19. Despite the potential of MM to improve SMEs' resilience, little evidence has been documented. Using Enterprise Survey data in Zambia, we show that SMEs are more likely than large firms to experience catastrophic sales decline, reflecting their inherent vulnerability. Further analysis reveals that this unfavourable effect can be effectively counteracted when SMEs incorporate MM into daily business. An important policy implication is that the use of digital technologies should be a key element of policy responses to Covid-19.

Deformable Photonic Crystals Based on Chiral Liquid Crystals with Thermal-Mediative Shape Memory Effect.

We propose a deformable photonic crystal that exhibits the thermal-mediative shape memory effect. The chiral liquid crystalline polymeric scaffold, which produces the structural colors from a helical twist of the liquid crystal director, is prepared through phase-stabilization of a reactive mesogen in a small molecular chiral liquid crystal (CLC), polymerization, and removal of the CLC. The prepolymer of polyurethane acrylate (PUA) is then infiltrated in the prepared scaffold and subsequently photo-polymerized to form a CLC-PUA composite film. Upon compression, this film shows the blue shift of the structural color and retains this color-shift as released from compression. As the temperature increases, the color is recovered to a pristine state. The concept proposed in this study will be useful for designing mechanochromic soft materials.

GALNT3 suppresses lung cancer by inhibiting myeloid-derived suppressor cell infiltration and angiogenesis in a TNFR and c-MET pathway-dependent manner.

The deregulation of polypeptide N-acetyl-galactosaminyltransferases (GALNTs) contributes to several cancers, but their roles in lung cancer remain unclear. In this study, we have identified a tumor-suppressing role of GALNT3 in lung cancer. We found that GALNT3 suppressed lung cancer development and progression in both xenograft and syngeneic mouse models. Specifically, GALNT3 suppressed lung cancer initiation by inhibiting the self-renewal of lung cancer cells. More importantly, GALNT3 attenuated lung cancer growth by preventing the creation of a favorable tumor microenvironment (TME), which was attributed to GALNT3's ability to inhibit myeloid-derived suppressor cell (MDSC) infiltration into tumor sites and subsequent angiogenesis. We also identified a GALNT3-regulated gene (GRG) signature and found that lung cancer patients whose tumors exhibit the GRG signature showed more favorable prognoses. Further investigation revealed that GALNT3 suppressed lung cancer cell self-renewal by reducing ß-catenin levels, which led to reduced expression of the downstream targets of the WNT pathway. In addition, GALNT3 inhibited MDSC infiltration into tumor sites by suppressing both the TNFR1-NFκB and cMET-pAKT pathways. Specifically, GALNT3 inhibited the nuclear localization of NFκB and the c-MET-induced phosphorylation of AKT. This then led to reduced production of CXCL1, a chemokine required for MDSC recruitment. Finally, we confirmed that the GALNT3-induced inhibition of the TNFR1-NFκB and cMET-pAKT pathways involved the O-GalNAcylation of the TNFR1 and cMET receptors. In summary, we have identified GALNT3 as the first GALNT member capable of suppressing lung cancer and uncovered a novel mechanism by which GALNT3 regulates the TME.

Sorption of anthracene (C14H10) and 9-anthroic acid (C15H10O2) onto biochar-amended soils as affected by field aging treatments.

There is a lack of information on how aging affects the sorption of ionizable organic compounds on biochar-amended soils. To that end, this study investigates the sorption of two hydrophobic solutes (anthracene (ANT) and 9-anthroic acid (9-ANCA)) onto biochar-amended (5%, w/w) soils as a function of aging period (0, 6, and 12 months), electrolyte (5 mM CaCl2 and 10 mM KCl), and aqueous pH. The isotherm plot of both solutes was fairly linear (r2 > 0.998) and the linear sorption coefficient (Kd, L kg-1) was obtained from this. In CaCl2 solution at pH 5, the log Kd of ANT tended to decrease (from 3.90 to 3.72) with an increasing aging period, which was attributed to clogged pore surface, whereas the differences in 9-ANCA sorption (from 2.56 to 2.51) were not significant (α = 0.05). The increased ANT sorption at acidic pH (<4) could be attributed to π-π interaction. Aqueous Ca2+ ions played an important role in 9-ANCA sorption by forming a Ca-bridge between anionic solute and negatively charged adsorbent surface, thus accounting for up to 35% of its sorption at alkaline pH (>8). The spectroscopic data and isoelectric point measurement results indicated that the number of oxygen-containing functional groups and the content of elemental oxygen were both higher in aged samples, resulting in a more polar (negatively charged) surface. The formation of surface polar groups and the associated deformation altered the adsorbent nature of the tested biochar, thereby fortifying the hydrophilic retention propensity for ionizable organic solutes.

PARP1 and PRC2 double deficiency promotes BRCA-proficient breast cancer growth by modification of the tumor microenvironment.

Poly (ADP-ribose) polymerase 1 (PARP1) and polycomb-repressive complex 2 (PRC2) are each known for their individual roles in cancer, but their cooperative roles have only been studied in the DNA damage repair process in the context of BRCA-mutant cancers. Here, we show that simultaneous inhibition of PARP1 and PRC2 in the MDA-MB-231 BRCA-proficient triple-negative breast cancer (TNBC) cell line leads to a synthetic viability independent of the mechanisms of DNA damage repair. Specifically, we find that either genetic depletion or pharmacological inhibition of both PARP1 and PRC2 can accelerate tumor growth rate. We attribute this to modifications in the tumor microenvironment (TME) that are induced by double-depleted breast cancer cells, such as promoting intratumoral angiogenesis and increasing the proportion of tumor-promoting type 2 (M2) macrophages. These changes subsequently inhibit cell death and promote proliferation. Mechanistically, we find that PARP1 and PRC2 double depletion induces not only a basal activation of the NF-κB pathway but also a maximal activation of NF-κB within the TME in response to external stimuli such as hypoxia and the presence of macrophages. In summary, our study reveals an unprecedented synthetic viable interaction between PARP1 and PRC2 in BRCA-proficient TNBC and identifies NF-κB as the downstream mediator. DATABASE: RNA-seq data are available in the GEO databases under the accession GSE142769.

Validation of the whole-body counting measurement in a radiation emergency.

Whole-body measurement can provide fast and accurate results in radiation emergencies. The whole-body counting method needs to be validated to guarantee the reliability and accuracy of the measurement. This study provides data related to the validation of the whole-body measurement using the stand-up type whole-body counter. Several parameters, including the sensitivity, accuracy, uncertainty, were considered for validation. The results indicate that the method of whole-body measurement is reliable for assessment of internal contamination.

Effect of HNO3 and H2SO4 on the Paddy Ecosystem: A Mesocosm Study with Exposure at PNEC and HC50 Levels.

Paddy mesocosms comprising of rice (Oryza sativa), snail (Pomacea canaliculata), and worm (Tubifex tubifex) were used to assess the damage caused by two acids (HNO3 and H2SO4) at predicted no-effect concentration (PNEC) and hazardous concentration for 50% of species (HC50) levels. In the fourth week, the fresh weight and shoot height of O. sativa at H2SO4-HC50 were reduced by 83.2% and 30.3%, respectively. Wilted leaves (%) at HC50 were approximately twice that at PNEC. No P. canaliculata and T. tubifex were recovered at HC50. At H2SO4-PNEC, the length and weight of P. canaliculata were reduced by 7.4% and 25.9%, respectively, whereas fewer adult (46.5%) and juvenile (84%) T. tubifex were recovered. In the 20th week, rice growth and productivity were correlated with initial pH (pHi) and nitrogen levels. Poor correlation with chlorophyll at the active tillering stage suggests the disturbance of nutrient uptake by roots. Partial least squares path modeling (PLS-PM) results further supported that the pHi directly affects grain yield and quality, as well as plant growth. The indirect effect via intervening fourth-week-variables was also substantial. Therefore, it is important to measure initial pH upon acid spill to estimate the risk to the paddy ecosystem. Information on the change in soil properties associated with acidity will also aid in predicting the yield and quality of grain to be harvested.

PRACTICAL METHODS FOR INTERNAL DOSE ASSESSMENT FOR RADIOIODINE INTAKE AFTER THYROID BLOCKING: CLASSIFICATION OF DEGREE OF BLOCKAGE AND DETERMINATION OF INSENSITIVE MEASUREMENT POINT.

Iodine thyroid blocking (ITB) suppresses the uptake of iodine to the thyroid and reduces internal doses after radioiodine intake; however, its disturbance of thyroid biokinetics causes considerable uncertainty in the use of dosimetric data intended for assessment of unblocked normal thyroid. To more accurately assess internal dose after ITB, practical dosimetry methods were proposed that consider the ITB effect in a dosimetric manner. A method using the ratio of urine excretion to thyroid retention activity was proposed to retrospectively determine individual-specific ITB levels; bioassay functions and dose coefficients corresponding to ITB levels were calculated separately using the latest biokinetic model and fundamental data. Moreover, insensitive measurement points of time, which led to similar results regardless of ITB level, were determined based on the dose per unit content. Proposed insensitive points for inhalation of vapour forms and particulate forms, respectively, were 1.5 days and 2 days after exposure.

Counting Efficiencies Determined by Monte Carlo Methods for In Vivo Measurement of 131I Activity in Thyroid.

The counting efficiencies obtained using a physical neck phantom are typically used in the measurement of I activity in the thyroid. It is well known, however, that the geometrical discrepancies between the physical neck phantom and the anatomy of the subject can significantly influence the counting efficiencies. Thus, it is necessary to consider the anatomical characteristics of individuals if we need to accurately determine the activity of I in the thyroid. This study aims to produce individualized counting efficiencies for thyroid measurement, considering the age, sex, and overlying tissue thickness of the subject being measured by Monte Carlo simulation. Simulations were performed using a series of computational human phantoms of different ages and sexes. The difference in counting efficiencies, depending on the age and sex of the phantom, were found to range from -26 to 3% for the phantoms and monitoring systems considered in the present study. The overlying tissue thickness of the computational phantoms was also modified to find the relationship between the counting ratio of the 80.2 and 364 keV gammas from I and the overlying tissue thickness. The equations for estimating the overlying tissue thickness of a subject were then derived from the relationships between counting ratios and overlying tissue thickness. Finally, in the present study, a set of equations representing the variation in counting efficiencies for the 364 keV peak as a function of the overlying tissue thickness were derived, which can be used to determine individualized counting efficiencies for the subject being measured. These individualized counting efficiencies considering the overlying tissue thickness given a subject's age and sex can provide accurate estimates of I activity for internal dosimetry.

Internal Dose Assessment after 131I-Iodide Misadministration in a Patient With Incompletely Blocked Thyroid Uptake: Personalized Internal Dose Assessment by Estimating Individual-Specific Biokinetics.

In July 2017, a medical accident occurred in South Korea, in which I-iodide solution was misadministered to the wrong patient. Although the International Commission on Radiological Protection provided internal dose coefficients for iodine for blocked thyroid, they were not reliable enough for determining the dose to the patient (whose thyroid uptake was incompletely blocked) due to a discrepancy in biokinetics. Therefore, a personalized dose assessment was performed to derive the individual-specific dose coefficients for the patient. Initially, the thyroid biokinetics of the patient were statistically clarified by fitting bioassay monitoring results and the corresponding predicted bioassay values, which were calculated repeatedly for varying iodine transfer rates in an iodine biokinetic model. After determining the transfer rate for the patient, the individual-specific dose coefficients were then calculated in accordance with latest recommendations of the International Commission on Radiological Protection. According to the individual-specific biokinetics, the 24 h thyroid uptake fraction of iodine was estimated as 0.52%. The thyroid absorbed dose of the patient was evaluated as 21.2 Gy, which differed greatly (by about 9 Gy) from the dose evaluated simply using the reference data for blocked thyroid uptake. The personalized dose assessment carried out for the patient not only reduced considerable uncertainties in the internal dose calculation, but also improved the reliability of the calculated internal dose by adopting the latest dosimetric data, including specific absorbed fraction values based on voxel phantoms. Through the dose assessment of the patient, the methodology of personalized dose assessment considering individual-specific biokinetics was developed.

Role of non-electrostatic forces in antimicrobial potency of a dengue-virus derived fusion peptide VG16KRKP: Mechanistic insight into the interfacial peptide-lipid interactions.

Cationic antimicrobial peptides (AMPs) are emerging as effective alternatives to conventional therapeutics that are used against the ever-rising number of multidrug-resistant microbial strains. Most studies established the peptide's amphipathicity and electrostatic interaction with the membrane as the basis for their antimicrobial effect. However, the interplay between the stoichiometric ratio of lipids, local geometry, diverse physicochemical properties of the host membranes and antimicrobial peptide efficacy is still poorly understood. In the present study, we investigate the mechanism of interaction of VG16KRKP (VARGWKRKCPLFGKGG), a novel AMP designed from the dengue-virus fusion peptide, with bacterial/fungal membrane mimics. Fluorescence based dye leakage assays show that membrane disruption is not solely induced by electrostatic interaction but also driven by stoichiometric ratio of the lipids that dictates the net surface charge, amount of lipid defects and local geometry of the membrane. Solid-state 14N and 31P NMR experiments show that peptide interaction results in lowering of lipid order around both the headgroups and acyl chains, suggesting deep peptide insertion. Further, an increase or decrease in membrane stability of the host membrane was observed in differential scanning calorimetry (DSC) thermograms, dictated by the overall stoichiometric ratio of the lipids and the sterol present. In general, our results help understand the diverse fates of host membranes against an antimicrobial peptide.

Measurement and Simulation of the Counting Efficiency of a Whole-body Counter Using a BOMAB Phantom Inserted with Rod Sources Containing Mixed Radionuclides.

The examination of internal contamination is important for providing an adequate medical response during a radiological emergency. A whole-body counting system can assess gamma-emitting radionuclides in a human body when monitoring internal contamination. It is necessary to calibrate whole-body counting systems by using a calibration phantom, such as a Bottle Manikin Absorption phantom, to properly assess internal contamination. However, the total weight of the Bottle Manikin Absorber phantom is high, and there can be leakage of radioactive sources, which are disadvantages of using such a phantom. This study proposes a calibration phantom that is designed to overcome these disadvantages. The proposed phantom consists of rod sources that are inserted in each part of the phantom. The counting efficiency of the rod-source-inserted calibration phantom was acquired using a Monte Carlo simulation method, but the results were evaluated by comparing the experimental efficiencies with those of a conventional Bottle Manikin Absorption phantom by using two commercial whole-body counting systems (stand-up type and bed type). The efficiency curve of the rod-source-inserted phantom matched well that of the conventional calibration phantom. The relative deviation between the efficiencies of the conventional Bottle Manikin Absorption phantom and the proposed calibration phantom in both whole-body counting systems was less than 11%, and the total weight of the phantom was also reduced. These results suggest that the proposed phantom can be manipulated more easily and replace the conventional Bottle Manikin Absorption calibration phantom for these two types of whole-body counting systems.

Caregiver Preference and Treatment Compliance in Patients with Mild-to-Moderate Alzheimer's Disease in South Korea: RECAP Study Results.

INTRODUCTION: The aim of this study was to assess caregiver preference and treatment compliance with oral and transdermal medications in a "real-world" setting in patients with mild-to-moderate Alzheimer's disease (AD) in South Korea. METHODS: Real-world evaluation of compliance and preference in Alzheimer's disease treatment (RECAP) was a 24-week, multicenter, prospective, non-interventional study in patients with AD treated with oral or transdermal therapy. Here, we report data from patients living in South Korea. Eligible patients were grouped into one of two treatment cohorts: oral (donepezil, galantamine, rivastigmine, or memantine) or transdermal (rivastigmine patch). Caregiver preference, patient compliance, and physician preference were assessed at week 24 (end of the study). Safety was assessed by reported adverse events (AEs). RESULTS: A total of 398 patients were enrolled (oral 51.8%; transdermal 48.2%) and 79.4% completed the study. Caregivers of patients that were exposed to either the oral or transdermal monotherapy showed a preference for the treatment to which the patients were exposed (both p < 0.0001). However, caregivers of patients that were exposed to both forms of treatments reported a higher preference for transdermal monotherapy (65.9%; p < 0.0041). Patients in both treatment cohorts showed good compliance, with an overall mean (SD) score of 8.84 (1.514) (a median of 9). Of the 15 participating physicians, eight indicated their preference for transdermal therapy and seven preferred oral therapy at week 24. A total of 133 (33.4%) patients reported at least one AE during the study period (oral: 60 patients; transdermal: 73 patients). CONCLUSION: The study showed higher caregiver preference for transdermal monotherapy over oral monotherapy when patients with AD were exposed to both forms of treatment and good patient compliance for both oral and transdermal treatments.

Monte Carlo simulation-based feasibility study of novel indirect flat panel detector system for removing scatter radiation.

The purpose of this study is to investigate the feasibility of a novel indirect flat panel detector (FPD) system for removing scatter radiation. The substrate layer of our FPD system has a Pb net-like structure that matches the ineffective area and blocks the scatter radiation such that only primary X-rays reach the effective area on a thin-film transistor. To evaluate the performance of the proposed system, we used Monte Carlo simulations to derive the scatter fraction and contrast. The scatter fraction of the proposed system is lower than that of a parallel grid system, and the contrast is superior to that of a system without a grid. If the structure of the proposed FPD system is optimized with respect to the specifications of a specific detector, the purpose of the examination, and the energy range used, the FPD can be useful in diagnostic radiology.

Hexane extract from Sargassum serratifolium inhibits the cell proliferation and metastatic ability of human glioblastoma U87MG cells.

The present study is the first to demonstrate the anticancer effects of a hexane extract from the brown algae Sargassum serratifolium (HES) on human cancer cell lines, including glioblastoma U87MG, cervical cancer HeLa and gastric cancer MKN-28 cells, as well as liver cancer SK-HEP 1 cells. Among these cancer cell lines, U87MG cells were most sensitive to the cell death induced by HES. HES exhibited a cytotoxic effect on U87MG cells at concentrations of 14-16 µg/ml, yet an effect was not observed in human embryonic kidney HEK293 cells. The antiproliferative effects of HES were regulated by inhibition of the MAPK/ERK signaling pathway which plays a pivotal role in the proliferation of glioblastoma U87MG cells. In addition, treatment with HES led to cell morphological changes and cell cytoskeleton degradation through regulation of actin dynamic signaling. Furthermore, migration and invasion of the U87MG cells were inhibited by HES via suppression of matrix metalloproteinase (MMP)-2 and -9 expression. Thus, our results suggest that HES is a potential therapeutic agent which has anticancer effects on glioblastoma.

Antimetastatic effects of gambogic acid are mediated via the actin cytoskeleton and NF-κB pathways in SK-HEP1 cells.

Hepatocellular carcinoma (HCC) is one of the most malignant and frequent cancers with a high metastatic potential. The prevention of HCC metastasis is a critical target for effective therapies in HCC. Gambogic acid (GA), a natural compound obtained from Garcinia hanburyi has reported anticancer activity in cell lines. However, the antimetastatic mechanisms of GA are unclear, particularly with respect to HCC. In this study, the influence of GA on migration and invasion of SK-HEP1 cells was evaluated. At concentrations above 0.6 µM, GA reduced cell proliferation in SK-HEP1 cells without affecting proliferation of noncancerous HEK-293 cells. GA also suppressed migration and invasion of SK-HEP1 cells. GA downregulated the expression of the integrin ß1/rho family GTPase signaling pathway, suppressed the actin rearrangement related to cell cytoskeleton and migration and decreased matrix metalloproteinases MMP-2, MMP-9, and NF-κB expression involved in cancer invasion. These results suggest that GA may be a potential lead in developing an antimetastatic therapeutic for the treatment of HCC.

Monte Carlo simulation-based feasibility study of a dose-area product meter built into a collimator for diagnostic X-ray.

According to the International Electro-technical Commission, manufacturers of X-ray equipment should indicate the number of radiation doses to which a patient can be exposed. Dose-area product (DAP) meters are readily available devices that provide dose indices. Collimators are the most commonly employed radiation beam restrictors in X-ray equipment. DAP meters are attached to the lower surface of a collimator. A DAP meter consists of a chamber and electronics. This separation makes it difficult for operators to maintain the accuracy of a DAP meter. Developing a comprehensive system that has a DAP meter in place of a mirror in the collimator would be effective for measuring, recording the dose and maintaining the quality of the DAP meter. This study was conducted through experimental measurements and a simulation. A DAP meter built into a collimator was found to be feasible when its reading was multiplied by a correction factor.