A randomized trial tested whether the addition of apalutamide, an androgen receptor blocker, to androgen-deprivation therapy might improve radiographic (including MRI-detected) progression–free ...survival and overall survival. Apalutamide was significantly more effective than placebo for both end points.
Advanced, metastatic melanomas frequently grow in subcutaneous tissues and portend a poor prognosis. Though subcutaneous tissues are largely composed of adipocytes, the mechanisms by which adipocytes ...influence melanoma are poorly understood. Using
and
models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. Additionally, adipocytes directly transfer lipids to melanoma cells, which alters tumor cell metabolism. Adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAF
in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. Pharmacologic blockade of FATPs with the small-molecule inhibitor Lipofermata abrogates lipid transport into melanoma cells and reduces melanoma growth and invasion. These data demonstrate that stromal adipocytes can drive melanoma progression through FATP lipid transporters and represent a new target aimed at interrupting adipocyte-melanoma cross-talk.
We demonstrate that stromal adipocytes are donors of lipids that mediate melanoma progression. Adipocyte-derived lipids are taken up by FATP proteins that are aberrantly expressed in melanoma. Inhibition of FATPs decreases melanoma lipid uptake, invasion, and growth. We provide a mechanism for how stromal adipocytes drive tumor progression and demonstrate a novel microenvironmental therapeutic target.
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The first interim analysis of the phase III, randomized, placebo-controlled TITAN study showed that apalutamide significantly improved overall survival (OS) and radiographic progression-free survival ...in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving ongoing androgen deprivation therapy (ADT). Herein, we report final efficacy and safety results after unblinding and placebo-to-apalutamide crossover.
Patients with mCSPC (N = 1,052) were randomly assigned 1:1 to receive apalutamide (240 mg QD) or placebo plus ADT. After unblinding in January 2019, placebo-treated patients were allowed to receive apalutamide. Efficacy end points were updated using the Kaplan-Meier method and Cox proportional-hazards model without formal statistical retesting and adjustment for multiplicity. Change from baseline in Functional Assessment of Cancer Therapy-Prostate total score was assessed.
With a median follow-up of 44.0 months, 405 OS events had occurred and 208 placebo-treated patients (39.5%) had crossed over to apalutamide. The median treatment duration was 39.3 (apalutamide), 20.2 (placebo), and 15.4 months (crossover). Compared with placebo, apalutamide plus ADT significantly reduced the risk of death by 35% (median OS not reached
52.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.79;
< .0001) and by 48% after adjustment for crossover (hazard ratio, 0.52; 95% CI, 0.42 to 0.64;
< .0001). Apalutamide plus ADT delayed second progression-free survival and castration resistance (
< .0001 for both). Health-related quality of life, per total Functional Assessment of Cancer Therapy-Prostate, in both groups was maintained through the study. Safety was consistent with previous reports.
The final analysis of TITAN confirmed that, despite crossover, apalutamide plus ADT improved OS, delayed castration resistance, maintained health-related quality of life, and had a consistent safety profile in a broad population of patients with mCSPC.
AMP protein kinase (AMPK) plays an important role in food intake and energy metabolism, which are synchronized to the light-dark cycle. In vitro, AMPK affects the circadian rhythm by regulating at ...least two clock components, CKIα and CRY1, via direct phosphorylation. However, it is not known whether the catalytic activity of AMPK actually regulates circadian rhythm in vivo.
THE CATALYTIC SUBUNIT OF AMPK HAS TWO ISOFORMS: α1 and α2. We investigate the circadian rhythm of behavior, physiology and gene expression in AMPKα1-/- and AMPKα2-/- mice. We found that both α1-/- and α2-/- mice are able to maintain a circadian rhythm of activity in dark-dark (DD) cycle, but α1-/- mice have a shorter circadian period whereas α2-/- mice showed a tendency toward a slightly longer circadian period. Furthermore, the circadian rhythm of body temperature was dampened in α1-/- mice, but not in α2-/- mice. The circadian pattern of core clock gene expression was severely disrupted in fat in α1-/- mice, but it was severely disrupted in the heart and skeletal muscle of α2-/- mice. Interestingly, other genes that showed circadian pattern of expression were dysreguated in both α1-/- and α2-/- mice. The circadian rhythm of nicotinamide phosphoryl-transferase (NAMPT) activity, which converts nicotinamide (NAM) to NAD+, is an important regulator of the circadian clock. We found that the NAMPT rhythm was absent in AMPK-deficient tissues and cells.
This study demonstrates that the catalytic activity of AMPK regulates circadian rhythm of behavior, energy metabolism and gene expression in isoform- and tissue-specific manners.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
How do women make sense of marriages that start with payments and brokers? This study explores the sustenance of connected lives through relational work by analyzing how women from Asia who ...marry South Korean men in transnationally brokered marriages understand money and marriage. Evidence from 31 in-depth interviews elucidates the different ways in which women manage their social and economic relations in their home country and their destination country, and how the negotiation of those ties impacts marriage decisions and experiences. The case extends our understanding of relational work by uncovering its dynamic nature as women’s changing expectations reconfigure their relations with family, brokers and husbands, and, in turn, reformulate their monetary practices. Examining women’s relational work also reveals micro-processes that underlie macro-level trends in the flow of money, information and people in Asia, lending an understanding of broader transnational processes.
The analysis of exhaled breath condensate (EBC) demonstrates a promising avenue of minimally invasive biopsies for diagnostics. EBC is obtained by cooling exhaled air and collecting the condensation ...to be utilized for downstream analysis using various analytical methods. The aqueous phase of breath contains a large variety of miscible small compounds including polar electrolytes, amino acids, cytokines, chemokines, peptides, small proteins, metabolites, nucleic acids, and lipids/eicosanoids—however, these analytes are typically present at minuscule levels in EBC, posing a considerable technical challenge. Along with recent improvements in devices for breath collection, the sensitivity and resolution of liquid chromatography coupled to online mass spectrometry‐based proteomics has attained subfemtomole sensitivity, vastly enhancing the quality of EBC sample analysis. As a result, proteomics analysis of EBC has been expanding the field of breath biomarker research. We present an au courant overview of the achievements in proteomics of EBC, the advancement of EBC collection devices, and the current and future applications for EBC biomarker analysis.
Redefining Multicultural Families in South Korea provides an in-depth look at the lives of families in Korea that include immigrants. Ten original chapters in this volume, written by scholars ...in multiple social science disciplines and covering different methodological approaches, aim to reinvigorate contemporary discussions about these multicultural families. Specially, the volume expands the scope of “multicultural families” by examining the diverse configurations of families with immigrants who crossed the Korean border during and after the 1990s, such as the families of undocumented migrant workers, divorced marriage immigrants, and the families of Korean women with Muslim immigrant husbands. Second, instead of looking at immigrants as newcomers, the volume takes a discursive turn, viewing them as settlers or first-generation immigrants in Korea whose post-migration lives have evolved and whose membership in Korean society has matured, by examining immigrants’ identities, need for political representation, their fights through the court system, and the aspirations of second-generation immigrants.
Abstract DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific ...genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.
Objective
To evaluate the efficacy and safety of apalutamide + androgen deprivation therapy versus androgen deprivation therapy alone in Japanese patients with metastatic castration‐sensitive ...prostate cancer from the phase 3, randomized, global TITAN study.
Methods
Men with metastatic castration‐sensitive prostate cancer randomly (1:1) received 240 mg apalutamide + androgen deprivation therapy or matching placebo + androgen deprivation therapy. The primary efficacy endpoints were radiographic progression‐free survival and overall survival. Secondary efficacy endpoints were time to cytotoxic chemotherapy, pain progression, chronic opioid use, and skeletal‐related events. Safety was also assessed.
Results
Of the 1052 patients included in the TITAN study, 51 (4.85%) were Japanese (apalutamide group, n = 28; placebo group, n = 23). In all, 81.8% of patients in the apalutamide and 71.8% in the placebo group did not experience radiographic progression or death, and the hazard ratio for radiographic progression‐free survival favored treatment with apalutamide (hazard ratio 0.712, 95% confidence interval 0.205–2.466; P = 0.59). At 24 months, 85.7% of patients in the apalutamide group and 81.5% in the placebo group were alive, and the hazard ratio for overall survival favored apalutamide (hazard ratio 0.840, 95% confidence interval 0.210–3.361; P = 0.805). In the interim analysis, the median radiographic progression‐free survival and overall survival were not reached in the apalutamide group and time to cytotoxic chemotherapy was delayed following apalutamide treatment. The safety profile of apalutamide in the Japanese subpopulation was comparable with that of the global population, except for skin rash.
Conclusions
The results of the present analyses suggest that apalutamide + androgen deprivation therapy in Japanese patients had favorable efficacy compared with androgen deprivation therapy alone, and these findings are comparable to those in the overall population. Apalutamide + androgen deprivation therapy can be considered as one of the therapeutic options for a broad spectrum of metastatic castration‐sensitive prostate cancer regardless of prior treatment and disease extent in Japanese patients.
Chiral plasmonic surfaces with 3D "forests" from nanohelicoids should provide strong optical rotation due to alignment of helical axis with propagation vector of photons. However, such ...three-dimensional nanostructures also demand multi-step nanofabrication, which is incompatible with many substrates. Large-scale photonic patterns on polymeric and flexible substrates remain unattainable. Here, we demonstrate the substrate-tolerant direct-write printing and patterning of silver nanohelicoids with out-of-plane 3D orientation using circularly polarized light. Centimeter-scale chiral plasmonic surfaces can be produced within minutes using inexpensive medium-power lasers. The growth of nanohelicoids is driven by the symmetry-broken site-selective deposition and self-assembly of the silver nanoparticles (NPs). The ellipticity and wavelength of the incident photons control the local handedness and size of the printed nanohelicoids, which enables on-the-fly modulation of nanohelicoid chirality during direct writing and simple pathways to complex multifunctional metasurfaces. Processing simplicity, high polarization rotation, and fine spatial resolution of the light-driven printing of stand-up helicoids provide a rapid pathway to chiral plasmonic surfaces, accelerating the development of chiral photonics for health and information technologies.
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