Real-world retrospective study of prostate-specific antigen and safety assessment with darolutamide plus androgen deprivation therapy for metastasis hormone-sensitive prostate cancer.

Background: ARASENS has demonstrated the efficacy and safety for darolutamide (DARO) with androgen deprivation therapy (ADT) plus docetaxel in metastasis hormone-sensitive prostate cancer (mHSPC). There is a lack of reports for DARO with ADT in mHSPC though the regimen is used in clinical from time to time. Moreover, recent studies have supported the importance of early and rapid prostate-specific antigen (PSA) reduction, which correlates with reduced disease progression and improved survival in patients with mHSPC. This study aims to evaluate PSA reduction as a primary endpoint for DARO with ADT in the treatment of mHSPC and to evaluate the real-world short-term PSA control of DARO with ADT from two leading medical centers in China. Methods: We retrospectively reviewed the clinical records of patients with mHSPC receiving ADT and DARO (600 mg, b.i.d.). The collection of data spanned from March 1, 2022, to July 31, 2023. The main observation indicators were PSA level and drug-related adverse events (AE) after medication. PSA levels were closely monitored prior to treatment initiation and at 2-week intervals, as well as at 1, 3, and 6 months after the initiation of treatment. We also conducted an analysis to determine the proportion of patients achieving a PSA reduction of 50% or more (PSA50) and 90% or more (PSA90) as well as the percentage of patients with a notable decrease in PSA level to 0.2 ng/mL and PSA nadir of ≤0.02 ng/mL. Results: Fifty-one patients were included in the study, with a median age of 73 years. At diagnosis of HSPC, the majority of patients had a Gleason score ≥8 (n=40, 78.40%) and a median baseline PSA level of 88 ng/mL. Approximately 45.1% (n=23) of patients had a Charlson Comorbidity Index over 1 and were receiving one or more nontumor-related treatments. The median follow-up time was 9.3 months (range, 1.16-15.8 months). The median reductions in PSA levels compared to baseline were 84.37%, 91.48%, 94.67% and 99.81% at 2 weeks, 1 month, 3 months and 6 months after administration of DARO with ADT, respectively. The median time to PSA50, PSA90, significant PSA reduction (PSA <0.2 ng/mL), and PSA nadir (PSA <0.02 ng/mL) was 0.97, 1.27, 1.98, and 2.08 months, respectively. AE mainly included fatigue (two patients) and arm pain (one patient), all of which were grade I or II AE. No grade III or AE were observed. Conclusions: For treating prostate cancer, DARO with ADT has good early efficacy, demonstrating prompt and substantial control of PSA levels, with a favorable safety profile.

Major HBV splice variant encoding a novel protein important for infection.

BACKGROUND & AIMS: HBV expresses more than 10 spliced RNAs from the viral pregenomic RNA, but their functions remain elusive and controversial. To address the function of HBV spliced RNAs, we generated splicing-deficient HBV mutants and conducted experiments to assess the impact of these mutants on HBV infection. METHODS: HepG2-NTCP cells, human hepatocyte chimeric FRG mice (hu-FRG mice), and serum from patients with chronic hepatitis B were used for experiments on HBV infection. Additionally, SHifter assays and cryo-electron microscopy were performed. RESULTS: We found the infectivity of splicing-deficient HBV was decreased 100-1,000-fold compared with that of wild-type HBV in hu-FRG mice. Another mutant, A487C, which loses the most abundant spliced RNA (SP1), also exhibits severely impaired infectivity. SP1 hypothetically encodes a novel protein HBcSP1 (HBc-Cys) that lacks the C-terminal cysteine from full-length HBc. In the SHifter assay, HBcSP1 was detected in wild-type viral particles at a ratio of about 20-100% vs. conventional HBc, as well as in the serum of patients with chronic hepatitis B, but not in A487C particles. When infection was conducted with a shorter incubation time of 4-8 h at lower PEG concentrations in HepG2-NTCP cells, the entry of the A487C mutant was significantly slower. SP1 cDNA complementation of the A487C mutant succeeded in rescuing its infectivity in hu-FRG mice and HepG2-NTCP cells. Moreover, cryo-electron microscopy revealed a disulfide bond between HBc cysteine 183 and 48 in the HBc intradimer of the A487C capsid, leading to a locked conformation that disfavored viral entry in contrast to the wild-type capsid. CONCLUSIONS: Prior studies unveiled the potential integration of the HBc-Cys protein into the HBV capsid. We confirmed the proposal and validated its identity and function during infection. IMPACT AND IMPLICATIONS: HBV SP1 RNA encodes a novel HBc protein (HBcSP1) that lacks the C-terminal cysteine from conventional HBc (HBc-Cys). HBcSP1 was detected in cell culture-derived HBV and confirmed in patients with chronic infection by both immunological and chemical modification assays at 10-50% of capsid. The splicing-deficient mutant HBV (A487C) impaired infectivity in human hepatocyte chimeric mice and viral entry in the HepG2-NTCP cell line. Furthermore, these deficiencies of the splicing-deficient mutant could be rescued by complementation with the SP1-encoded protein HBcSP1. We confirmed and validated the identity and function of HBcSP1 during infection, building on the current model of HBV particles.

An ensemble learning-based feature selection algorithm for identification of biomarkers of renal cell carcinoma.

Feature selection plays a crucial role in classification tasks as part of the data preprocessing process. Effective feature selection can improve the robustness and interpretability of learning algorithms, and accelerate model learning. However, traditional statistical methods for feature selection are no longer practical in the context of high-dimensional data due to the computationally complex. Ensemble learning, a prominent learning method in machine learning, has demonstrated exceptional performance, particularly in classification problems. To address the issue, we propose a three-stage feature selection algorithm framework for high-dimensional data based on ensemble learning (EFS-GINI). Firstly, highly linearly correlated features are eliminated using the Spearman coefficient. Then, a feature selector based on the F-test is employed for the first stage selection. For the second stage, four feature subsets are formed using mutual information (MI), ReliefF, SURF, and SURF* filters in parallel. The third stage involves feature selection using a combinator based on GINI coefficient. Finally, a soft voting approach is proposed to employ for classification, including decision tree, naive Bayes, support vector machine (SVM), k-nearest neighbors (KNN) and random forest classifiers. To demonstrate the effectiveness and efficiency of the proposed algorithm, eight high-dimensional datasets are used and five feature selection methods are employed to compare with our proposed algorithm. Experimental results show that our method effectively enhances the accuracy and speed of feature selection. Moreover, to explore the biological significance of the proposed algorithm, we apply it on the renal cell carcinoma dataset GSE40435 from the Gene Expression Omnibus database. Two feature genes, NOP2 and NSUN5, are selected by our proposed algorithm. They are directly involved in regulating m5c RNA modification, which reveals the biological importance of EFS-GINI. Through bioinformatics analysis, we shows that m5C-related genes play an important role in the occurrence and progression of renal cell carcinoma, and are expected to become an important marker to predict the prognosis of patients.

The importance of electrolyte environment during in situ self-transformation for synthesizing V2O5·nH2O.

V2O5·nH2O is a promising cathode material for zinc-ion batteries. One of the synthesis methods of V2O5·nH2O is in situ self-transformation. In this communication, we focus on the influence of the electrolyte environment during in situ self-transformation (from VO2 to V2O5·nH2O). 2 M ZnSO4 and 2 M Zn(OTf)2 were used as different electrolytes to produce VOH-1 and VOH-2. VOH-1 expands in volume along the electric field to form a porous surface structure and shows low crystallinity along the (0 0 1) plane, while VOH-2 exhibits the opposite. These advantages enable the assembled batteries with VOH-1 to maintain excellent cycling performance at a rate of 2 A g-1 with a capacity of 500 mA h g-1 and stable cycling for 1800 cycles.

RCC2 promotes prostate cancer cell proliferation and migration through Hh/GLI1 signaling pathway and cancer stem-like cells.

BACKGROUND: Regulator of chromosome condensation 2 (RCC2) was a telophase disk-binding protein on mitosis, and functions as an oncogene in many human cancers. However, its role on prostate cancer (PCa) was unknown. The goal of this study is to explore the function of RCC 2 on PCa development. METHODS: The expression of RCC2 and its methylation level, its correlation with lymph node metastasis or disease-free survival (DFS) was analyzed using TCGA database. The effect of RCC2 on PCa cell proliferation, migration and invasion were detected using CCK-8, cell colony formation, Transwell and wood healing assays. RNA-seq and GSEA analysis were used to search the downstream genes and pathways of RCC2 in mediated PCa progression. Western blot was used to detect the proteins in PCa cells transfected with indicated siRNAs or plasmids. RESULTS: RCC2 had high expression and low promoter methylation level in PCa, and its expression was correlated with regional node metastasis and disease-free survival. Cell proliferation, migration, invasion and EMT of PCa cells in vitro were greatly enhanced after RCC2 overexpression, while the RCC2 knockdown suppressed these processes. RNA-seq and GSEA results showed the Hedgehog signaling regulator Gli1 and Gli3 were involved in RCC2 knockdown DU145 cells. Gli1 was also a marker of cancer stem-like cells (CSCs). Mechanistically, RCC2 induced cell growth, EMT, CSCs markers through Gli1; inhibiting Gli1 expression using siGli1 or GLI inhibitor suppressed cell progression in vitro and tumor growth in vivo. CONCLUSION: In summary, RCC2 promoted PCa development through Hh/Gli1 signaling pathway via regulating EMT and CSCs.

Racial disparities in conditional survival of patients with bladder cancer: a population-based study.

BACKGROUND: Traditional estimates can only provide static predictions of cancer outcomes and cannot assess the evolving effect of race on patient survival. This study aims to reveal the dynamic survival of patients with bladder cancer and to explore the evolving effect of race on patient prognosis. METHODS: Using data from the Surveillance, Epidemiology, and End Results (SEER) registry, 99,590 white, 6,036 African American, and 4,685 Asian/Pacific Islander (API) patients with bladder cancer were identified. Conditional cancer-specific survival (CSS) rates, which could reflect the dynamic survival prediction of cancer patients, represented the primary outcomes, and were estimated by the Kaplan-Meier algorithm. The evolving effect of race on patient survival was evaluated by multivariable Cox regression in combination with conditional survival (CS) estimates. RESULTS: The 5-year CSS for African American patients who had survived 1, 2, 3, 4, or 5 years after definitive therapy improved from the baseline calculation by + 5.8 (84.4%), + 9.5 (87.4%), + 12.8 (90.0%), + 14.4 (91.3%), and + 14.7% (91.5%), respectively. The increasing trend also held for overall white and API patients, and for all patient subsets when CS was calculated according to different levels of sex, age, and disease stage. African Americans, despite having the worst survival at baseline, could have CSS comparable to their white and API counterparts after 4 years of survivorship. In addition, the risk of death for African Americans tended to decrease with increasing survival, and the risk was no longer significantly different from that of whites after 4 years of survival. CONCLUSIONS: While having the worst initial predicted outcomes, African Americans may eventually achieve comparable survival to white and API patients given several years of survivorship. As patient survival increases, African American race may lose its role as an indicator of poorer prognosis.

Roles of hydrogen bonding interactions and hydrophobic effects on enhanced water structure in aqueous solutions of amphiphilic organic molecules.

Insights into the solute-induced water structural transformations are essential to understand the role of water in biological and chemical reaction processes. Herein, the structural changes in water induced by amphiphilic organic molecules were investigated using concentration-dependent derivative Raman spectroscopy (DRS) combined with two-dimensional Raman correlation spectroscopy (2D Raman-COS). We shall restrict our attention in this work to binary mixtures of water with dimethyl sulfoxide (DMSO), acetone, and isopropanol (IPA), all of which have similar chemical structures. The spectral changes in O:H and OH stretching modes illustrate that the solute molecules induce an enhancement of the water structure in dilute solutions, where the enhanced degree of water structure is closely related to the size of the dipole moment of organic molecules. In addition, the transformations of solute-induced water-specific structures were evaluated by 2D Raman-COS, which shows that the strong hydrogen bond (H-bond) structure of water is more sensitive to organic molecules and induces a transition to the weak H-bond structure of water.

Tau protein plays a role in the mechanism of cognitive disorders induced by anesthetic drugs.

Cognitive disorders are mental health disorders that can affect cognitive ability. Surgery and anesthesia have been proposed to increase the incidence of cognitive dysfunction, including declines in memory, learning, attention and executive function. Tau protein is a microtubule-associated protein located in the axons of neurons and is important for microtubule assembly and stability; its biological function is mainly regulated by phosphorylation. Phosphorylated tau protein has been associated with cognitive dysfunction mediated by disrupting the stability of the microtubule structure. There is an increasing consensus that anesthetic drugs can cause cognitive impairment. Herein, we reviewed the latest literature and compared the relationship between tau protein and cognitive impairment caused by different anesthetics. Our results substantiated that tau protein phosphorylation is essential in cognitive dysfunction caused by anesthetic drugs, and the possible mechanism can be summarized as "anesthetic drugs-kinase/phosphatase-p-Tau-cognitive impairment".

Exploring electronic energy level structure and excited electronic states of ß-carotene using DFT.

Carotenoids are a class of natural pigments that play a fundamental role in photosynthesis and optoelectronics. However, the complexity of their energy level structure and electronic states has prevented a clear interpretation of their photophysics and photochemistry. The mediating nonradiative decay of the bright S2 state to the dark S1 state of carotenoids involves a population of bridging intermediate state. Herein, time-dependent DFT was used to study the energy level and electronic excitation process of ß-carotene. A π-π* transition and π electron delocalization of electron excitation could be inferred based on the difference in the electron cloud distribution of the HOMO and LUMO orbitals. Through the electronic transition contribution in the UV-vis spectra and the electron density difference between the ground state and the excited state, the electronic energy level structure and possible dark state were analyzed. On this basis, the electronic excitation process of ß-carotene was theoretically studied by combining electron-hole analysis and transition density matrix (TDM). There was a charge transfer from the ß-ionone ring to the long-chain in the (S0) → (S2), (S0) → (S4) and (S0) → (S5).

Intermolecular energy transfer-enhanced super-broadband stimulated Raman scattering in cyclohexane-benzene mixtures.

Supercontinuum radiation has found numerous applications in diverse fields encompassing spectroscopy, pulse compression, and tunable laser sources. Anomalous enhanced stimulated Raman scattering (SRS) of cyclohexane-benzene mixtures was obtained in this study. SRS of the pure solvent, the multi-order Stokes of the strongest fundamental vibration modes, and energy transfer in intra-molecular modes were observed. SRS of the mixture revealed that the cross-pumping effect was generated between the C-H stretching (v2) mode of cyclohexane and the C=C ring skeleton (v1) mode of benzene, thereby producing the intermolecular secondary stimulated Raman emission and the appearance of two super-broadband radiations at 664.36-673.9 nm and 704.62-729.22 nm. The results suggest that the energy transfer of intermolecular vibrational modes, where the strongest vibrational mode excites other vibrational modes, is a simple approach for generating supercontinuum coherent radiation.

Hydrogen bond network dynamics of heavy water resolved by alcohol hydration under an intense laser.

Despite a great deal of effort spanning for decades, it remains yet puzzling concerning how alcohol molecules functionalize the hydrogen bond (H-bond) networks of water. We employed an isotopic substitution method (using alcohol-heavy water system) to avoid spectral overlap between the alcohol hydroxyl groups and water hydrogen bonds. We showed spectrometrically that under the strong pulse laser, the low mixing ratio (VA < 20%) of alcohol can strengthen the H-bond network structure of D2O through :ÖC2H6↔ D2Ö: compression. But when VA > 20%, H-bond network of D2O will deform via the self-association between alcohol molecules. Our experiments not only reveal the H-bond kinetics of heavy water-alcohol interactions but also provide important reference for understanding the distinctive properties of H-bond in water-organic system.

Single-Position Complete Retroperitoneoscopic Radical Nephroureterectomy with Bladder Cuff Excision for Upper Urinary Tract Urothelial Carcinoma.

Purpose: We proposed a new technique, single-position complete retroperitoneoscopic radical nephroureterectomy (SCRNU), which proved to be efficient for the treatment of upper urinary tract urothelial carcinoma (UTUC). Materials and Methods: In this study, we retrospectively evaluated 86 patients diagnosed with UTUC at our hospital from June 2013 to June 2021. The patients who underwent traditional retroperitoneoscopic nephroureterectomy (TRNU) (n = 28) and SCRNU (n = 58) were consecutively enrolled. Demographic characteristics, perioperative parameters, and follow-up data were collected and compared between the two groups. Results: Both procedures were performed effectively in 86 patients without converting to open surgery. The mean follow-up time was 45.4 months for the SCRNU group and 39 months for the TRNU group. All follow-up patients survived without incidence of bladder incision tumor. Further, the follow-up results showed that there was no significant difference in the recurrence rate of bladder tumor between the two methods. SCRNU group was superior to TRNU group because of shorter operating time, fewer perioperative complications, less postoperative pain, lower recurrence rate, and cheaper medical expenditure. Conclusions: The SCRNU technique is less invasive, have fewer complications, and has a better cosmetic outcome.

Hydrogen bonding network dynamics of 1,2-propanediol-water binary solutions by Raman spectroscopy and stimulated Raman scattering.

Raman spectroscopy and stimulated Raman scattering (SRS) were used to investigate the hydrogen bonding (HB) network in 1,2-propanediol (1,2-PD)-water binary solutions. Abnormal changes in hydrogen bonds (HBs) were detected when V1,2-PD (volume fraction of the1,2-PD) was 0.4. In the case of Raman spectroscopy, the HB strength of water is weakened and then strengthened with the increase of 1,2-PD volume fraction. In the case of SRS, two new peaks at 3283 cm-1 and 3319 cm-1 were appeared, which demonstrated the appearance of ice-like structures near the methyl group and the weakening of HBs. Based on these phenomena, the HB structure of this binary system underwent a transition from H2O-H2O to H2O-1,2-PD when the V1,2-PD was 0.4 as V1,2-PD increased. This work serves as a reference value for the study of HB networks in alcohol-water binary solutions.

Efficient frequency conversion and the crossing-pump effect of stimulated Raman scattering in an aqueous sodium sulfate solution.

The cascaded stimulated Raman scattering (SRS) of an aqueous sodium sulfate solution was investigated as well as the generation of the crossing-pump effect. With the introduction of dual sample cells, the first-order Stokes of the O-H stretching vibrational mode was able to act as the pump light to excite the Stokes of the S-O stretching vibrational mode, and a new Raman peak was obtained at 4423 cm-1. The dual sample cell device not only lowered the SRS threshold, but also enhanced the four-wave mixing (FWM) process. Compared to the input laser of 7 ns/pulse, the first-order Stokes of O-H was compressed to a pulse width of 413 ps after passing through the dual sample cells. The SRS of aqueous sodium sulfate solution covered an ultrabroad wavelength ranging from 441 nm to 720 nm (a Raman shift ranging from -3859 cm-1 to 4923 cm-1). The cone-shaped launch ring of the FWM process was also recorded. This work provides a reference for the establishment of laser frequency conversion devices using an aqueous sodium sulfate solution as the Raman medium.

Sex differences in myelination of the zebra finch vocal control system emerge relatively late in development.

The role of myelination in the development of motor control is widely known, but its role in the development of cognitive abilities is less understood. Here, we examined sex differences in the development of myelination of structures and tracts that support song learning and production in songbirds. We collected brains from 63 young male and female zebra finches (Taeniopygia guttata) over four stages of development that correspond to different stages of song learning. Using a myelination marker (myelin basic protein), we measured the development of myelination in three different nuclei of the vocal control system (HVC, RA, and lateral magnocellular nucleus of the anterior nidopallium [LMAN]) and two tracts (HVC-RA and lamina mesopallium ventralis [LMV]). We found that the myelination of the vocal control nuclei and tracts is sex related and male biased. In males, the patterns of myelination were age-dependent, asynchronous in rate and progression and associated with the development of song learning and production. In females, myelination of vocal control nuclei was low or absent and did not significantly change with age. Sex differences in myelination of the HVC-RA tract were large and emerged late in development well after sex differences in the size of vocal control brain regions are established. Myelination of this tract in males coincides with the age of song crystallization. Overall, the changes in myelination in the vocal control areas and tracts measured are region-, age-, and sex-specific and are consistent with sex differences in song development.

Modulated excited state geometry and Electron-Phonon coupling of lutein by temperature and solvent polarizability.

Resonance Raman spectroscopy is one of the spectroscopic methods often chosen for studying linear polyene molecules because the Raman intensities of their υ1 (C = C) and υ2 (C-C) stretching vibrations are sensitive to electron-phonon coupling and the π-electron energy gap. Here, the resonance Raman and absorption spectra of lutein were studied as a function of solvent polarizabilities and of temperature in the CS2 solvent. For lutein in CS2, as the temperature decreased and CS solidified, the Raman scattering cross-section (RSCS) and the electron-phonon coupling constant had opposite dependence trends on temperature. The wavenumber of the lutein 0-0 electronic transition showed a marked shift to lower wavenumbers when the polarizability of the solvents decreased, and the Huang-Rhys (HR) factors and electron-phonon coupling also decreased. This work helps explore the influence of the external environment (e.g., temperature and solvent) on the excited state geometry of linear polyene molecules.

Efficiency moderates the relationship between sleep-onset insomnia and resting-state electroencephalogram microstate.

BACKGROUND: Overactivation of the salience network (SN) causes hyperarousal in insomnia patients and is associated with sleep-onset insomnia (SOI). Resting-state microstate 3 (RS-MS3) duration is closely related to SN overactivation. However, whether RS-MS3 duration is a biomarker for SOI has not yet been reported in the literature. In addition, SN activity is also associated with efficiency. However, it is not clear whether there are individual differences in the neural mechanisms of SOI in different efficiency groups. METHODS: Considering that RS-MS3 duration characterizes the stability and persistent activation of the SN in the resting state, the current study investigated the link between SOI measured by sleep latency of Pittsburg Sleep Quality Index (PSQI), efficiency measured by Kirton Adaption-Innovation Inventory (KAI), and RS-MS3 in a Chinese healthy (subclinical) student population, using electroencephalography (EEG) microstate analysis. RESULTS: We found that RS-MS3 duration was positively correlated with sleep latency and efficiency. The interaction between sleep latency and efficiency was significant. Simple slope analysis showed that high sleep latency was positively correlated with longer RS-MS3 duration in participants with higher efficiency scores. This correlation did not exist in participants with low efficiency scores. CONCLUSIONS: RS-MS3 duration may serve as a biomarker for SOI. There is heterogeneity in the relationship between SOI and RS-MS3 duration between individuals with high and low efficiency.

Electrochemical Activation of Oxygen Vacancy-Rich Nitrogen-Doped Manganese Carbonate Microspheres for High-Performance Aqueous Zinc-Ion Batteries.

Aqueous zinc-ion batteries (ZIBs) are considered as one of the ideal devices for large-scale energy storage because of their safety, low cost, and nontoxicity. Unfortunately, the choice of cathode materials for ZIBs is still limited. Herein, a novel oxygen vacancy-rich nitrogen-doped MnCO3 (MnCO3@N) microsphere is reported as a cathode material for rechargeable ZIBs, which displays a relatively high reversible capacity of 171.6 mAh g-1 at 100 mA g-1, outstanding rate performance, and long-term cyclic stability up to 1000 cycles at 1000 mA g-1. The better electrochemical performances of MnCO3@N should be attributed to the introduction of oxygen vacancies in the MnCO3 microcrystal by nitrogen doping, which not only improves the conductivity of MnCO3 microspheres but also creates more active sites for zinc-ion diffusion. In addition, the energy storage mechanism of the MnCO3@N microspheres is systematically investigated. During the initial charge process, the MnCO3@N microspheres are activated to form MnO@N due to the insertion of Zn2+, and partial MnO@N is further oxidized into layered-type MnO2@N, which becomes a part of the active material for subsequent energy storage. This work not only provides a new insight for the ZIB cathode but also deepens the understanding of the energy storage mechanism of carbonate materials.