Single-nucleotide polymorphism-based genetic risk score and patient age at prostate cancer diagnosis

Importance: Few studies have evaluated the association between a single-nucleotide polymorphism-based genetic risk score (GRS) and patient age at prostate cancer (PCa) diagnosis. Objectives: To test the association between a GRS and patient age at PCa diagnosis and to compare the performance of a GRS with that of family history (FH) in PCa risk stratification. Design, Setting, and Participants: A cohort study of 3225 white men was conducted as a secondary analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) chemoprevention trial, a 4-year, randomized, double-blind, placebo-controlled multicenter study conducted from March 2003 to April 2009 to evaluate the safety and efficacy of dutasteride in reducing PCa events. Participants were confirmed to be cancer free by prostate biopsy (6-12 cores) within 6 months prior to the study and underwent 10 core biopsies every 2 years per protocol. The dates for performing data analysis were from July 2016 to October 2019. Interventions: A well-established, population-standardized GRS was calculated for each participant based on 110 known PCa risk-associated single-nucleotide polymorphisms, which is a relative risk compared with the general population. Men were classified into 3 GRS risk groups based on predetermined cutoff values: low (\u3c0.50), average (0.50-1.49), and high (≥1.50). Main Outcomes and Measures: Prostate cancer diagnosis-free survival among men of different risk groups. Results: Among 3225 men (median age, 63 years [interquartile range, 58-67 years]) in the study, 683 (21%) were classified as low risk, 1937 (60%) as average risk, and 605 (19%) as high risk based on GRS alone. In comparison, 2789 (86%) were classified as low or average risk and 436 (14%) as high risk based on FH alone. Men in higher GRS risk groups had a PCa diagnosis-free survival rate that was worse than that of those in the lower GRS risk group (χ2 = 53.3; P \u3c .001 for trend) and in participants with a negative FH of PCa (χ2 = 45.5; P \u3c .001 for trend). Combining GRS and FH further stratified overall genetic risk, indicating that 957 men (30%) were at high genetic risk (either high GRS or positive FH), 1667 men (52%) were at average genetic risk (average GRS and negative FH), and 601 men (19%) were at low genetic risk (low GRS and negative FH). The median PCa diagnosis-free survival was 74 years (95% CI, 73-75 years) for men at high genetic risk, 77 years (95% CI, 75 to \u3e80 years) for men at average genetic risk, and more than 80 years (95% CI, \u3e80 to \u3e80 years) for men at low genetic risk. In contrast, the median PCa diagnosis-free survival was 73 years (95% CI, 71-76 years) for men with a positive FH and 77 years (95% CI, 76-79 years) for men with a negative FH. Conclusions and Relevance: This study suggests that a GRS is significantly associated with patient age at PCa diagnosis. Combining FH and GRS may better stratify inherited risk than FH alone for developing personalized PCa screening strategies

Autocrine, Not Paracrine, Interferon-Gamma Gene Delivery Enhances Ex Vivo Antigen-Specific Cytotoxic T Lymphocyte Stimulation and Killing

The adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTL) shows promise in the treatment of cancer and infectious diseases. We utilize adeno-associated virus-(AAV-) based antigen gene-loaded dendritic cells (DCs) to stimulate such antigen-specific CTL. Yet further improvements in CTL stimulation and killing may result by gene delivery of various Th1-response interferons/cytokines, such as interferon γ (IFN-γ), as the delivered gene can continuously produce that interferon. However which immune cell type should optimally express IFN-γ is unclear as the phenotypes of both DC and T cells are enhanced by it. Here, we used AAV to compare and contrast IFN-γ gene delivery into DC or T cells, and versus the addition of exogenous IFN-γ, for stimulating carcinoembryonic antigen-(CEA-) specific CTL. It was found that AAV/IFN-γ delivery into T cells (autocrine) resulted in T cell populations with the highest CD8(+)/CD4(+) ratio, highest IFN-γ(+)/IL-4(+) ratio, highest CD69(+),CD8(+) levels, and lowest CD4(+)/CD25(+) levels, all consistent with the strongest Th1 response. Most importantly, AAV/IFN-γ transduction of T cells resulted in antigen-specific T cell populations with the highest killing capabilities, 49% above other treatments. These data strongly suggest that AAV/IFN-γ autocrine gene delivery into T cells is worthy of further study towards maximizing the generation of antigen-specific anticancer CTL killers

Can a Flexibility/Support Initiative Reduce Turnover Intentions and Exits? Results from the Work, Family, and Health Network

We draw on panel data from a randomized field experiment to assess the effects of a flexibility/supervisor support initiative called STAR on turnover intentions and voluntary turnover among professional technical workers in a large firm. An unanticipated exogenous shock-the announcement of an impending merger-occurred in the middle of data collection. Both organizational changes reflect an emerging employment contract characterized by increasing employee temporal flexibility even as employers wield greater flexibility in reorganizing their workforces. We theorized STAR would reduce turnover intentions and actual turnover by making it more attractive to stay with the current employer. We found being in a STAR team (versus a usual practice team) lowered turnover intentions 12 months later and reduced the risk of voluntary turnover over almost three years. We also examined potential mechanisms accounting for the effects of these two organizational changes; STAR effects on reducing turnover intentions are partially mediated by reducing work-to-family conflict, family-to-work conflict, burnout, psychological distress, perceived stress, and increasing job satisfaction. The effect of learning about the merger on increasing turnover intentions is fully mediated by increased job insecurity. STAR also moderates the negative effects of learning about the merger on turnover intentions for different subgroups. Findings provide insights into the effectiveness of an organizational intervention, the dynamics of organizations, and how competing logics of two organizational changes affect employees' labor market expectations and behavior

Iron oxide nanoparticles induce human microvascular endothelial cell permeability through reactive oxygen species production and microtubule remodeling

<p>Abstract</p> <p>Background</p> <p>Engineered iron nanoparticles are being explored for the development of biomedical applications and many other industry purposes. However, to date little is known concerning the precise mechanisms of translocation of iron nanoparticles into targeted tissues and organs from blood circulation, as well as the underlying implications of potential harmful health effects in human.</p> <p>Results</p> <p>The confocal microscopy imaging analysis demonstrates that exposure to engineered iron nanoparticles induces an increase in cell permeability in human microvascular endothelial cells. Our studies further reveal iron nanoparticles enhance the permeability through the production of reactive oxygen species (ROS) and the stabilization of microtubules. We also showed Akt/GSK-3β signaling pathways are involved in iron nanoparticle-induced cell permeability. The inhibition of ROS demonstrate ROS play a major role in regulating Akt/GSK-3β – mediated cell permeability upon iron nanoparticle exposure. These results provide new insights into the bioreactivity of engineered iron nanoparticles which can inform potential applications in medical imaging or drug delivery.</p> <p>Conclusion</p> <p>Our results indicate that exposure to iron nanoparticles induces an increase in endothelial cell permeability through ROS oxidative stress-modulated microtubule remodeling. The findings from this study provide new understandings on the effects of nanoparticles on vascular transport of macromolecules and drugs.</p

Conductance and persistent current of a quantum ring coupled to a quantum wire under external fields

The electronic transport of a noninteracting quantum ring side-coupled to a quantum wire is studied via a single-band tunneling tight-binding Hamiltonian. We found that the system develops an oscillating band with antiresonances and resonances arising from the hybridization of the quasibound levels of the ring and the coupling to the quantum wire. The positions of the antiresonances correspond exactly to the electronic spectrum of the isolated ring. Moreover, for a uniform quantum ring the conductance and the persistent current density were found to exhibit a particular odd-even parity related with the ring-order. The effects of an in-plane electric field was also studied. This field shifts the electronic spectrum and damps the amplitude of the persistent current density. These features may be used to control externally the energy spectra and the amplitude of the persistent current.Comment: Revised version, 7 pages and 9 figures. To appear in Phys. Rev.

A cohort study of the efficacy and safety of immune checkpoint inhibitors plus anlotinib versus immune checkpoint inhibitors alone as the treatment of advanced non-small cell lung cancer in the real world

BACKGROUND: Anlotinib is a new multi-target tyrosine kinase inhibitor (TKI) and has been shown to have antitumor effects and synergistic antitumor effects with immunotherapy only in animal studies and in the 2nd-line treatment in small clinical trials. A real-world study with large sample to compare the efficacy and safety of anlotinib plus immune checkpoint inhibitors (ICIs) with ICIs alone in the multiline treatment of advanced non-small cell lung cancer (NSCLC) was urgently needed. METHODS: The data of 535 advanced NSCLC patients were collected from January 1, 2018, to December 31, 2021. The patients were divided into 2 groups: (I) ICI monotherapy (230 patients); (II) ICI + anlotinib (305 patients). After propensity-score matching (PSM) to reduce the effects of biases and confounding variables, the progression-free survival time (PFS), occurrence of adverse events, disease control rate (DCR), and objective response rate (ORR) of the 2 groups were compared. The effects of clinical factors, including age, gender, gene mutations, tumor proportion score, metastases, and combined radiotherapy, were also analyzed. RESULTS: After PSM, the baseline clinical characteristics were well balanced and the 2 group had a good comparability. Patients in the ICI + anlotinib group had significantly longer median PFS in both the 2nd-line treatment (7.73 vs. 4.70 months; P=0.003) and 3rd-line treatment (5.90 vs. 3.37 months; P=0.020), but the difference lacked statistical significance in the 1st-line treatment (8.40 vs. 5.20 months; P=0.229). The overall median PFS of patients in the ICI + anlotinib group was also much longer than that of patients in the ICI monotherapy group (6.37 vs. 3.90 months; P<0.001). The ICI + anlotinib group also tended to have a higher DCR, a higher ORR, and a higher probability of severe adverse drug reactions during the treatment than the ICI monotherapy group, but the differences were not statistically significant. Combining ICI + anlotinib could improve the outcomes of patients with bone metastasis. CONCLUSIONS: Anlotinib + ICI therapy could have greater efficacy in the treatment of advanced NSCLC patients than ICI monotherapy. The probability of adverse events might increase in the combined treatment, but could be controlled

Antitumor agents 290. Design, synthesis, and biological evaluation of new LNCaP and PC-3 cytotoxic curcumin analogs conjugated with anti-androgens

In our continuing study of curcumin analogs as potential anti-prostate cancer drug candidates, 15 new curcumin analogs were designed, synthesized and evaluated for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Twelve analogs (5-12, 15, 16, 19, and 20) are conjugates of curcumin (1) or methyl curcumin (2) with a flutamide- or bicalutamide-like moiety. Two compounds (22 and 23) are C4-mono- and difluoro-substituted analogs of dimethyl curcumin (DMC, 21). Among the newly synthesized conjugates compound 15, a conjugate of 2 with a partial bicalutamide moiety, was more potent than bicalutamide alone and essentially equipotent with 1 and 2 against both prostate tumor cell lines with IC50 values of 41.8 μM (for LNCaP) and 39.1 μM (for PC-3). A cell morphology study revealed that the cytotoxicity of curcumin analogs or curcumin-antiandrogen conjugates detected from both prostate cancer cell lines might be due to the suppression of pseudopodia formation. A molecular intrinsic fluorescence experiment showed that 1 accumulated mainly in the nuclei, while conjugate 6 was distributed in the cytosol. At the tested conditions, antiandrogens suppressed pseudopodia formation in PC-3 cells, but not in LNCaP cells. The evidence suggests that distinguishable target proteins are involved, resulting in the different outcomes toward pseudopodia suppression

The Solar Twin Planet Search. V. Close-in, low-mass planet candidates and evidence of planet accretion in the solar twin HIP 68468

[Methods]. We obtained high-precision radial velocities with HARPS on the ESO 3.6 m telescope and determined precise stellar elemental abundances (~0.01 dex) using MIKE spectra on the Magellan 6.5m telescope. [Results]. Our data indicate the presence of a planet with a minimum mass of 26 Earth masses around the solar twin HIP 68468. The planet is a super-Neptune, but unlike the distant Neptune in our solar system (30 AU), HIP 68468c is close-in, with a semi-major axis of 0.66 AU, similar to that of Venus. The data also suggest the presence of a super-Earth with a minimum mass of 2.9 Earth masses at 0.03 AU; if the planet is confirmed, it will be the fifth least massive radial velocity planet discovery to date and the first super-Earth around a solar twin. Both isochrones (5.9 Gyr) and the abundance ratio [Y/Mg] (6.4 Gyr) indicate an age of about 6 billion years. The star is enhanced in refractory elements when compared to the Sun, and the refractory enrichment is even stronger after corrections for Galactic chemical evolution. We determined a NLTE Li abundance of 1.52 dex, which is four times higher than what would be expected for the age of HIP 68468. The older age is also supported by the low log(R'HK) (-5.05) and low jitter. Engulfment of a rocky planet of 6 Earth masses can explain the enhancement in both lithium and the refractory elements. [Conclusions]. The super-Neptune planet candidate is too massive for in situ formation, and therefore its current location is most likely the result of planet migration that could also have driven other planets towards its host star, enhancing thus the abundance of lithium and refractory elements in HIP 68468. The intriguing evidence of planet accretion warrants further observations to verify the existence of the planets that are indicated by our data and to better constrain the nature of the planetary system around this unique star.Comment: A&A, in pres

Electrophysiological Studies in Thyroid Associated Orbitopathy: A Systematic Review

Dysthyroid optic neuropathy (DON) is the commonest cause of blindness in thyroid associated orbitopathy (TAO). While diagnosis remains clinical, objective tests for eyes with early or equivocal findings are lacking. Various electrophysiological studies (EPS) have been reported, yet the types and parameters useful for DON remain inconclusive. We performed a systematic literature search in MEDLINE, EMBASE and the Cochrane databases via the OVID platform up to August 20, 2017. 437 records were identified for screening and 16 original studies (1327 eyes, 787 patients) were eligible for review. Pattern visual evoked potential (pVEP) was the most frequently studied EPS. Eyes of TAO patients with DON showed delayed P100 latencies, decreased P100 amplitudes or delayed N75 latencies during pVEP, compared to those without or healthy controls. Due to study heterogeneity, no quantitative analysis was possible. This review highlights the most common type (pVEP) and useful parameters (P100 latency and amplitude) of EPS, and supports further research on them using standardized testing conditions