The abscopal effect could theoretically be potentiated when combined with immunomodulating drugs through increased antigen production. The optimal dosing and schedule of radiotherapy with ...immunotherapy are unknown, although they are actively investigated in laboratory and clinical models. Clinical data in patients treated for metastatic disease with both modalities may guide future studies.
This is a single-institution retrospective review of all patients treated with stereotactic body radiotherapy (SBRT)/stereotactic radiosurgery (SRS) and immunomodulating therapy within 6 months before or after SBRT/SRS for metastatic cancer. Clinical and tumor characteristics were recorded, as well as SBRT/SRS details, immunotherapy details, and survival. Log-rank tests on Kaplan-Meier curves for overall survival (OS) that were calculated from the end of SBRT/SRS were used in univariate analysis and Cox proportional hazards regression for multivariate analysis.
A total of 125 patients were identified who met the inclusion criteria; 70 received SBRT, and 57 received SRS. Eighty-three patients were treated for non-small cell lung cancer, 7 patients for small cell lung cancer, and 35 patients for other cancers, with the most common one being melanoma. Fifty-three percent of patients received nivolumab, 29% pembrolizumab, 13% atezolizumab, 5% other. Twenty percent received immunotherapy before SBRT/SRS, 39% during SBRT/SRS, 41% after. Eighty-six patients had died by the time of the analysis; the median OS for the whole cohort was 9.7 months. Patients who had completed immunotherapy prior to SBRT/SRS had worse OS than those who received concurrent therapy or immunotherapy after SBRT/SRS, with a difference in median OS of 3.6 months vs. 13.0 months (p = 0.010) that was retained on multivariate analysis (p = 0.011). There was no significant difference in OS between patients receiving SRS vs. SBRT (p = 0.20), sex (p = 0.53), age >62 years (p = 0.76), or lung primary vs. others (p = 0.73) on univariate or multivariate analysis. When comparing before/concurrent to after/concurrent administration, there is a difference in survival with after/concurrent survival of 8.181 months and before survival of 13.010 months, but this was not significant (p = 0.25).
OS appears to be worse in patients who complete immunotherapy prior to SBRT/SRS compared to those receiving it concurrently or after. The design of this retrospective review may be prone to lead time bias, although the difference in median survival is longer than the 6-month window before SBRT/SRS and could only account for part of this difference. Further analysis into causes of death and toxicity and prospective studies are needed to confirm the results of this analysis.
Heparin is a polysaccharide-based natural product that is used clinically as an anticoagulant drug. Heparan sulfate 3-O-sulfotransferase (3-OST) is an enzyme that transfers a sulfo group to the 3-OH ...position of a glucosamine unit. 3-OST is present in multiple isoforms, and the polysaccharides modified by these different isoforms perform distinct biological functions. 3-OST isoform 1 (3-OST-1) is the key enzyme for the biosynthesis of anticoagulant heparin. Here, we report the crystal structure of the ternary complex of 3-OST-1, 3'-phosphoadenosine 5'-phosphate, and a heptasaccharide substrate. Comparisons to previously determined structures of 3-OST-3 reveal unique binding modes used by the different isoforms of 3-OST for distinguishing the fine structures of saccharide substrates. Our data demonstrate that the saccharide substrates display distinct conformations when interacting with the different 3-OST isoforms. Site-directed mutagenesis data suggest that several key amino residues, including Lys259, Thr256, and Trp283 in 3-OST-3 and Arg268 in 3-OST-1, play important roles in substrate binding and specificity between isoforms. These results deepen our understanding of the biosynthetic mechanism of heparan sulfate and provide structural information for engineering enzymes for an enhanced biosynthetic approach to heparin production.
A polymerization reaction was employed as a signal amplification method to realize direct visualization of gender-specific DNA extracted from human blood in a polymerase chain reaction (PCR)-free ...fashion. Clear distinction between X and Y chromosomes was observed by naked eyes for detector-free sensing purposes. The grown polymer films atop X and Y chromosomes were quantitatively measured by ellipsometry for thickness readings. Detection assays have been optimized for genomic DNA recognition to a maximum extent by varying the selection of the proper blocking reagents, the annealing temperature, and the annealing time. Traditional PCR and gel electrophoresis for amplicon identification were conducted in parallel for performance comparison. In the blind test for blood samples examined by the new approach, 25 out of 26 were correct and one was false negative, which was comparable to, if not better than, the PCR results. This is the first time our amplification-by-polymerization technique is being used for chromosome DNA analysis. The potential of adopting the described sensing technique without PCR was demonstrated, which could further promote the development of a portable, PCR-free DNA sensing device for point-of-need applications.
Heparin is a highly sulfated polysaccharide that is commercially available for anticoagulation. As an animal sourced product, heparin is heterogeneous and contains polysaccharides that differ in ...length and sulfation patterns. In 2007, heparin sourced from porcine intestines was contaminated with over-sulfated chondroitan sulfate. Taken in conjunction with other possible pharmacological activities, there have been efforts to synthesize distinct heparan sulfate polysaccharides in a cost-effective manner, including chemoenzymatic synthesis. Some of the limitations associated with chemoenzymatic synthesis include expensive starting materials and incomplete synthesis leading to a product mixture. In an effort to overcome the first obstacle we developed two methods to efficiently synthesize the starting materials for heparan sulfate chemoenzymatic synthesis, including UDP-GlcNTFA and UDP-GlcA, from glucosamine and glucose respectively. To overcome the second obstacle, we explored possible inhibition by the chemoenzymatic co-factor PAPS. Both of these projects aim to advance the production of heparin and heparan sulfate polysaccharides.
Transcultural nursing theory (Leininger, 1995) goes beyond or transcends cultural boundaries, and examining and cultivates an appreciation of human beings, their cultures, histories, and values. ...Assessment of values, histories, needs, and expectations assists in providing culturally competent patient care. Transcultural nursing courses are an integral part of nursing education. The qualitative study examines perceptions of 6 Associate of Science in Nursing students related to transcultural nursing experiences in college and clinical education. This study explores what influence, if any, gender has in their experiences. The interpretive study uses semistructured interviewing during focus group and interview meetings. The interviewer solicited responses on behaviors, feelings, and knowledge related to transcultural nursing concepts. Participants maintained a diary of transcultural nursing experiences for 2 weeks. Thematic development coding techniques employed provide detailed descriptions of their experiences. Two themes emerged: self awareness and respect for individuals. This research will aid nurse educators by explicating students' perceptions of transcultural nursing experiences.
Because I work at a small firm, I’ve kept track of security for the firm for many years. ...I’ve come to specialize in Windows and Office patches and am one of the moderators of the mailing list at ...patchmanagement.org. ...some of my computers are on 1909, a.k.a. the Windows 10 November 2019 Update, whereas others are running 2004, a.k.a. the Windows 10 May 2020 Update. First back up everything, then follow the steps in the Windows Update Assistant.
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