Complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT).
To determine if stereotactic ablative ...radiotherapy (SABR) improves oncologic outcomes in men with oligometastatic prostate cancer.
The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized study accrued participants from 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6 months of enrollment or 3 or more years total were randomized.
Patients were randomized in a 2:1 ratio to receive SABR or observation.
The primary outcome was progression at 6 months by prostate-specific antigen level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at 6 months with SABR, progression-free survival, Brief Pain Inventory (Short Form)-measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)-targeted positron emission tomography in the identification of metastatic disease.
In the 54 men randomized, the median (range) age was 68 (61-70) years for patients allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (P = .005). Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). No toxic effects of grade 3 or greater were observed. T-cell receptor sequencing identified significant increased clonotypic expansion following SABR and correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P = .03).
Treatment with SABR for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by PSMA-targeted positron emission tomography. SABR induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates.
ClinicalTrials.gov Identifier: NCT02680587.
The title compound, a novel 30‐membered 2:2 macrocyclic thiocarbohydrazone, C34H32N8O4S2·3C5H5N, has been prepared and crystallographically characterized. The molecule of the compound is twisted. ...One dioxabutane group is boat‐like in shape, whereas the other is highly disordered. The crystal structure is stabilized by inter‐ and intramolecular hydrogen bonds.
Snake venom is a cocktail of hundreds to thousands of biologically active proteins and enzymes used in both attack and defense. Because these proteins are capable of modulating the physiological ...response of envenomated animals, they show promise as potential pharmacological tools and as drug leads. In order to study function and structure relationships of snake venom proteins, many protein expression systems, including E. coli, yeast, baculovirus infected insect cells, mammalian cells, and cell-free protein synthesis, were used to produce recombinant proteins. Many venom proteins cannot be expressed in E. coli with the correct fold because most of them are highly disulfide-bonded. In contrast, many proteins have been successfully expressed in eukaryotic systems. Even though eukaryotic expression systems may allow the expression of proteins with the correct fold, they have certain disadvantages. For example, most proteins obtained from these expression systems are expensive, time consuming to produce, and are in low yield. Recently the methylotrophic yeast Pichia pastoris has drawn a lot of attention because it combines several advantages of prokaryotic and eukaryotic expression systems. It is the only system that offers the quality of E. coli like high level expression, easy scale up, and inexpensive growth medium combined with the advantages of expression in a eukaryotic system (protein processing, folding, and posttranslational modifications). Therefore, the P. pastoris expression system has been used to produce a variety of heterologous proteins. The P. pastoris system has also been widely used to express many snake venom proteins. The focus of this review will summarize the results of snake venom toxins expressed in P. pastoris.
Summary
Heat stress has profound effects on animal performance and muscle function, and microRNAs (miRNAs) play a critical role in muscle development and stress responses. To characterize the changes ...in miRNAs in skeletal muscle responding to heat stress, the miRNA expression profiles of longissimus dorsi muscles of pigs raised under constant heat stress (30 °C; n = 8) or control temperature (22 °C; n = 8) for 21 days were analyzed by Illumina deep sequencing. A total of 58 differentially expressed miRNAs were identified with 30 down‐regulated and 28 up‐regulated, and 63 differentially expressed target genes were predicted by miRNA–mRNA joint analysis. GO and KEGG analyses showed that the genes regulated by differentially expressed miRNAs were enriched in glucose metabolism, cytoskeletal structure and function and stress response. Real‐time PCR showed that the mRNA levels of PDK4, HSP90 and DES were significantly increased, whereas those of SCD and LDHA significantly decreased by heat exposure. The protein levels of CALM1, DES and HIF1α were also significantly increased by constant heat. These results demonstrated that the change in miRNA expression in porcine longissimus dorsi muscle underlies the changes in muscle structure and metabolism in porcine skeletal muscle affected by constant heat stress.
A series of α-Fe2O3/ZnO composites with different α-Fe2O3 contents were successfully prepared by a simple and rapid method. The products were characterized by XRD, FESEM and UV–vis DRS. ...Photocatalytic activity of the as-prepared α-Fe2O3/ZnO composites was evaluated by degradation of persistent organic pollutant pentachlorophenol (PCP) in aqueous solution. Compared with pure ZnO, α-Fe2O3/ZnO composites show higher photocatalytic activity under UV–vis light irradiation. PCP is almost completely degraded by α-Fe2O3/ZnO composite with molar ratio 1:5 within 4h.
Surgical resection remains the prefer option for bladder cancer treatment. However, the effectiveness of surgery is usually limited for the high recurrence rate and poor prognosis. Consequently, ...intravesical chemotherapy synergize with immunotherapy in situ is an attractive way to improve therapeutic effect. Herein, a combined strategy based on thermo-sensitive PLEL hydrogel drug delivery system was developed. GEM loaded PLEL hydrogel was intravesical instilled to kill tumor cells directly, then PLEL hydrogel incorporated with CpG was injected into both groins subcutaneously to promote immune responses synergize with GEM. The results demonstrated that drug loaded PLEL hydrogel had a sol-gel phase transition behavior in response to physiological temperature and presented sustained drug release, and the PLEL-assisted combination therapy could have better tumor suppression effect and stronger immunostimulating effect in vivo. Hence, this combined treatment with PLEL hydrogel system has great potential and suggests a clinically-relevant and valuable option for bladder cancer.
A combined strategy based on thermo-sensitive PLEL hydrogel drug delivery system for bladder cancer was developed. GEM loaded PLEL hydrogel was intravesical instilled firstly, then PLEL hydrogel incorporated with CpG was injected into both groins subcutaneously to promote immune responses. Results demonstrated that drug loaded PLEL hydrogel had a sol-gel phase transition behavior and presented sustained drug release, and the PLEL-assisted combination therapy could have better tumor suppression effect and stronger immunostimulating effect in vivo. Display omitted
•The triblock polymer PDLLA-PEG-PDLLA (PLEL) is a thermos-sensitive hydrogel for localized drug delivery.•Drug loaded PLEL hydrogel achieves the sustained release of drug and extend retention time of Gemcitabine in bladder.•Intravesical chemotherapy with immunothrapy by thermo-sensitive PLEL system improves anti-tumor effect for bladder cancer.•Combined therapy strategy assisted by PLEL hydrogel promote related immune response to help kill bladder cancer cells.
Synovial joint development begins with the formation of the interzone, a region of condensed mesenchymal cells at the site of the prospective joint. Recently, lineage-tracing strategies have revealed ...that Gdf5-lineage cells native to and from outside the interzone contribute to most, if not all, of the major joint components. However, there is limited knowledge of the specific transcriptional and signaling programs that regulate interzone formation and fate diversification of synovial joint constituents. To address this, we have performed single cell RNA-Seq analysis of 7329 synovial joint progenitor cells from the developing murine knee joint from E12.5 to E15.5. By using a combination of computational analytics,
hybridization and
characterization of prospectively isolated populations, we have identified the transcriptional profiles of the major developmental paths for joint progenitors. Our freely available single cell transcriptional atlas will serve as a resource for the community to uncover transcriptional programs and cell interactions that regulate synovial joint development.
Stars form out of the densest parts of molecular clouds. Far-IR emission can be used to estimate the star formation rate (SFR) and high dipole moment molecules, typically HCN, trace the dense gas. A ...strong correlation exists between HCN and far-IR emission, with the ratio being nearly constant, over a large range of physical scales. A few recent observations have found HCN to be weak with respect to the far-IR and CO in subsolar metallicity (low-Z) objects. We present observations of the Local Group galaxies M 33, IC 10, and NGC 6822 with the IRAM 30 m and NRO 45 m telescopes, greatly improving the sample of low-Z galaxies observed. HCN, HCO+, CS, C2H, and HNC have been detected. Compared to solar metallicity galaxies, the nitrogen-bearing species are weak (HCN, HNC) or not detected (CN, HNCO, N2H+) relative to far-IR or CO emission. HCO+ and C2H emission is normal with respect to CO and far-IR. While 13CO is the usual factor 10 weaker than 12CO, C18O emission was not detected down to very low levels. Including earlier data, we find that the HCN/HCO+ ratio varies with metallicity (O/H) and attribute this to the sharply decreasing nitrogen abundance. The dense gas fraction, traced by the HCN/CO and HCO+/CO ratios, follows the SFR but in the low-Z objects the HCO+ is much easier to measure. Combined with larger and smaller scale measurements, the HCO+ line appears to be an excellent tracer of dense gas and varies linearly with the SFR for both low and high metallicities.
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