Comparison of survival outcomes between olaparib and niraparib maintenance therapy in BRCA-mutated, newly diagnosed advanced ovarian cancer.

INTRODUCTION: This multicenter retrospective cohort study aimed to compare survival outcomes and adverse events between maintenance therapy with two poly (ADP-ribose) polymerase (PARP) inhibitors, olaparib and niraparib, in patients with BRCA-mutated, newly diagnosed advanced epithelial ovarian cancer (EOC) who responded to platinum-based chemotherapy. METHODS: We enrolled stage III-IV EOC patients with germline and/or somatic BRCA1/2 mutations that had received maintenance therapy with olaparib or niraparib. A 3:1 propensity score matching was conducted using two variables: residual disease size and the presence of germline variants. The primary outcome was progression-free survival (PFS), and the secondary outcomes were time to first subsequent therapy (TFST), overall survival (OS), and treatment-emergent adverse events (TEAEs). RESULTS: In the propensity score-matched analysis, 80 patients who received olaparib and 31 patients who received niraparib were matched (3:1). In the propensity score-matched cohort, median PFS with olaparib vs. niraparib was not reached vs 31.5 months (HR, 1.08; 95% CI, 0.47-2.52; p = 0.854). The median TFST was not reached vs 31.8 months (HR, 1.20; 95% CI, 0.51-2.81; p = 0.682), and neither olaparib nor niraparib reached the median OS (HR, 0.42; 95% CI, 0.01-17.61; p = 0.649). In terms of the incidence rates of any-grade hematologic or non-hematologic TEAEs, higher rates of thrombocytopenia (p = 0.021) and neutropenia (p = 0.011) were observed in the niraparib group. CONCLUSION: Advanced EOC patients with BRCA1/2 mutations exhibited no significant difference in OS between olaparib and niraparib, indicating the need to consider individualized strategies for selecting PARP inhibitors based on adverse event profiles.

Association of Pre- and Post-Donation Renal Function with Midterm Estimated Glomerular Filtration Rate in Living Kidney Donors: A Retrospective Study.

PURPOSE: The estimated glomerular filtration rate (eGFR) at 6 months after donation (eGFR6m) is strongly associated with the risk of end-stage renal disease in living kidney donors. This study aimed to investigate the incidence of eGFR6m <60 mL/min/1.73 m² (eGFR6m <60) and identify the risk factors that can predict the occurrence of eGFR6m <60 in living kidney donors. MATERIALS AND METHODS: Living kidney donors who underwent nephrectomy at Severance Hospital between January 2009 and December 2019 were identified. We excluded 94 of 1233 donors whose creatinine values at 6 months after donation were missing. The risk factors for eGFR6m <60 were assessed using multivariate regression analysis. The optimal cutoff points for candidate risk factors for predicting eGFR6m <60 occurrence were determined using the Youden index. RESULTS: The eGFR6m <60 occurred in 17.3% of the participants. Older age (≥44 years), history of hypertension, lower preoperative eGFR (<101 mL/min/1.73 m²), and degree of increase in creatinine levels on postoperative day 2 compared to those before surgery (ΔCr2_pre) (≥0.39 mg/dL) increased the risk of eGFR6m <60. The addition of ΔCr2_pre to preoperative eGFR yielded a higher predictive accuracy for predicting eGFR6m <60 than that with preoperative eGFR alone {area under the receiver operating characteristic curve=0.886 [95% confidence interval (CI), 0.863-0.908] vs. 0.862 (95% CI, 0.838-0.887), p<0.001}. CONCLUSION: The incidence of eGFR6m <60 was 17.3%. Older age, lower preoperative eGFR, history of hypertension, and greater ΔCr2_pre were associated with the occurrence of eGFR6m <60 after living donor nephrectomy. The combination of preoperative eGFR and ΔCr2_pre showed the highest predictive power for eGFR6m <60.

Spatial modeling of geogenic indoor radon distribution in Chungcheongnam-do, South Korea using enhanced machine learning algorithms.

Prolonged inhalation of indoor radon and its progenies lead to severe health problems for housing occupants; therefore, housing developments in radon-prone areas are of great concern to local municipalities. Areas with high potential for radon exposure must be identified to implement cost-effective radon mitigation plans successfully or to prevent the construction of unsafe buildings. In this study, an indoor radon potential map of Chungcheongnam-do, South Korea, was generated using a group method of data handling (GMDH) algorithm based on local soil properties, geogenic, geochemical, as well as topographic factors. To optimally tune the hyper-parameters of GMDH and enhance the prediction accuracy of modelling radon distribution, the GMDH model was integrated with two metaheuristic optimization algorithms, namely the bat (BA) and cuckoo optimization (COA) algorithms. The goodness-of-fit and predictive performance of the models was quantified using the area under the receiver operating characteristic (ROC) curve (AUC), mean squared error (MSE), root mean square error (RMSE), and standard deviation (StD). The results indicated that the GMDH-COA model outperformed the other models in the training (AUC = 0.852, MSE = 0.058, RMSE = 0.242, StD = 0.242) and testing (AUC = 0.844, MSE = 0.060, RMSE = 0.246, StD = 0.0242) phases. Additionally, using metaheuristic optimization algorithms improved the predictive ability of the GMDH. The GMDH-COA model showed that approximately 7 % of the total area of Chungcheongnam-do consists of very high radon-prone areas. The information gain ratio method was used to assess the predictive ability of considered factors. As expected, soil properties and local geology significantly affected the spatial distribution of radon potential levels. The radon potential map produced in this study represents the first stage of identifying areas where large proportions of residential buildings are expected to experience significant radon levels due to high concentrations of natural radioisotopes in rocks and derived soils beneath building foundations. The generated map assists local authorities to develop urban plans more wisely towards region with less radon concentrations.

Amplification of olfactory signals by Anoctamin 9 is important for mammalian olfaction.

Sensing smells of foods, prey, or predators determines animal survival. Olfactory sensory neurons in the olfactory epithelium (OE) detect odorants, where cAMP and Ca2+ play a significant role in transducing odorant inputs to electrical activity. Here we show Anoctamin 9, a cation channel activated by cAMP/PKA pathway, is expressed in the OE and amplifies olfactory signals. Ano9-deficient mice had reduced olfactory behavioral sensitivity, electro-olfactogram signals, and neural activity in the olfactory bulb. In line with the difference in olfaction between birds and other vertebrates, chick ANO9 failed to respond to odorants, whereas chick CNGA2, a major transduction channel, showed greater responses to cAMP. Thus, we concluded that the signal amplification by ANO9 is important for mammalian olfactory transduction.

Anoctamin 1/TMEM16A in pruritoceptors is essential for Mas-related G protein receptor-dependent itch.

ABSTRACT: Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that anoctamin 1 (ANO1), a Ca 2+ -activated chloride channel, is a transduction channel mediating Mrgpr-dependent itch signals. Genetic ablation of Ano1 in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgpr-dependent itch models and the epidermal hyperplasia induced by dry skin. In vivo Ca 2+ imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgprs excited DRG neurons via ANO1. More importantly, the overexpression of Ano1 in DRG neurons of Ano1 -deficient mice rescued the impaired itching observed in Ano1 -deficient mice. These results demonstrate that ANO1 mediates the Mrgpr-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes.

Tentonin 3/TMEM150C senses blood pressure changes in the aortic arch.

The baroreceptor reflex is a powerful neural feedback that regulates arterial pressure (AP). Mechanosensitive channels transduce pulsatile AP to electrical signals in baroreceptors. Here we show that tentonin 3 (TTN3/TMEM150C), a cation channel activated by mechanical strokes, is essential for detecting AP changes in the aortic arch. TTN3 was expressed in nerve terminals in the aortic arch and nodose ganglion (NG) neurons. Genetic ablation of Ttn3 induced ambient hypertension, tachycardia, AP fluctuations, and impaired baroreflex sensitivity. Chemogenetic silencing or activation of Ttn3+ neurons in the NG resulted in an increase in AP and heart rate, or vice versa. More important, overexpression of Ttn3 in the NG of Ttn3-/- mice reversed the cardiovascular changes observed in Ttn3-/- mice. We conclude that TTN3 is a molecular component contributing to the sensing of dynamic AP changes in baroreceptors.

One-Step Laser Patterned Highly Uniform Reduced Graphene Oxide Thin Films for Circuit-Enabled Tattoo and Flexible Humidity Sensor Application.

The conversion of graphene oxide (GO) into reduced graphene oxide (rGO) is imperative for the electronic device applications of graphene-based materials. Efficient and cost-effective fabrication of highly uniform GO films and the successive reduction into rGO on a large area is still a cumbersome task through conventional protocols. Improved film casting of GO sheets on a polymeric substrate with quick and green reduction processes has a potential that may establish a path to the practical flexible electronics. Herein, we report a facile deposition process of GO on flexible polymer substrates to create highly uniform thin films over a large area by a flow-enabled self-assembly approach. The self-assembly of GO sheets was successfully performed by dragging the trapped solution of GO in confined geometry, which consisted of an upper stationary blade and a lower moving substrate on a motorized translational stage. The prepared GO thin films could be selectively reduced and facilitated from the simple laser direct writing process for programmable circuit printing with the desired configuration and less sample damage due to the non-contact mode operation without the use of photolithography, toxic chemistry, or high-temperature reduction methods. Furthermore, two different modes of the laser operating system for the reduction of GO films turned out to be valuable for the construction of novel graphene-based high-throughput electrical circuit boards compatible with integrating electronic module chips and flexible humidity sensors.

Anoctamin 9/TMEM16J is a cation channel activated by cAMP/PKA signal.

Anoctamins (ANOs) are multifunctional membrane proteins that consist of 10 homologs. ANO1 (TMEM16A) and ANO2 (TMEM16B) are anion channels activated by intracellular calcium that meditate numerous physiological functions. ANO6 is a scramblase that redistributes phospholipids across the cell membrane. The other homologs are not well characterized. We found ANO9/TMEM16J is a cation channel activated by a cAMP-dependent protein kinase A (PKA). Intracellular cAMP-activated robust currents in whole cells expressing ANO9, which were inhibited by a PKA blocker. A cholera toxin that persistently stimulated adenylate cyclase activated ANO9 as did the application of PKA. The cAMP-induced ANO9 currents were permeable to cations. The cAMP-dependent ANO9 currents were augmented by intracellular Ca2+. Ano9 transcripts were predominant in the intestines. Human intestinal SW480 cells expressed high levels of Ano9 transcripts and showed PKA inhibitor-reversible cAMP-dependent currents. We conclude that ANO9 is a cation channel activated by a cAMP/PKA pathway and could play a role in intestine function.