Immunogenic camptothesome nanovesicles comprising sphingomyelin-derived camptothecin bilayers for safe and synergistic cancer immunochemotherapy.

Despite the enormous therapeutic potential of immune checkpoint blockade (ICB), it benefits only a small subset of patients. Some chemotherapeutics can switch 'immune-cold' tumours to 'immune-hot' to synergize with ICB. However, safe and universal therapeutic platforms implementing such immune effects remain scarce. We demonstrate that sphingomyelin-derived camptothecin nanovesicles (camptothesomes) elicit potent granzyme-B- and perforin-mediated cytotoxic T lymphocyte (CTL) responses, potentiating PD-L1/PD-1 co-blockade to eradicate subcutaneous MC38 adenocarcinoma with developed memory immunity. In addition, camptothesomes improve the pharmacokinetics and lactone stability of camptothecin, avoid systemic toxicities, penetrate deeply into the tumour and outperform the antitumour efficacy of Onivyde. Camptothesome co-load the indoleamine 2,3-dioxygenase inhibitor indoximod into its interior using the lipid-bilayer-crossing capability of the immunogenic cell death inducer doxorubicin, eliminating clinically relevant advanced orthotopic CT26-Luc tumours and late-stage B16-F10-Luc2 melanoma, and achieving complete metastasis remission when combined with ICB and folate targeting. The sphingomyelin-derived nanotherapeutic platform and doxorubicin-enabled transmembrane transporting technology are generalizable to various therapeutics, paving the way for transformation of the cancer immunochemotherapy paradigm.

Supervising pharmacists' opinions about pharmacy technicians as immunizers.

OBJECTIVES: To determine the opinions of pharmacists who supervise immunizing pharmacy technicians regarding initial trust of immunizing technicians, perceived quality of the training program, need for additional on-the-job training, frequency of technician utilization, and recommendations for other pharmacists who are considering implementation of an immunizing technician. SETTING: Albertsons pharmacies located in the state of Idaho in May 2017. PRACTICE DESCRIPTION AND INNOVATION: Qualitative descriptive study of semistructured key informant interviews with Idaho pharmacists who currently supervise a pharmacy technician trained to administer immunizations. EVALUATION: Informant interviews were recorded, transcribed, and coded to evaluate key themes. RESULTS: Nineteen individual pharmacist interviews were conducted at different Albertsons pharmacy locations in the state of Idaho. Pharmacists in this study felt that their immunizing technicians were properly trained to administer immunizations, capable of giving immunizations, and empowered by their new role within the pharmacy. Participants expressed challenges with initial comfort in allowing a technician to immunize, support of this new advanced technician role, and additional on-the-job training for individual technicians. Findings also included a pharmacist-perceived increase in vaccination rates and recommendation for other technicians to be trained to administer immunizations. CONCLUSION: Community pharmacists who supervise pharmacy technicians trained to administer immunizations were receptive to this new advanced technician role. Pharmacists' opinions revealed that working with newly trained immunizing pharmacy technicians has not only positively affected the morale of their team, but can help to increase the number of vaccinations given by the pharmacy. Understanding pharmacist perceptions about technicians as immunizers may lead to regulation changes and adoption of this advanced technician role.

Brassinosteroid signaling converges with SUPPRESSOR OF PHYTOCHROME B4-#3 to influence the expression of SMALL AUXIN UP RNA genes and hypocotyl growth.

Interactions between signaling pathways help guide plant development. In this study, we found that brassinosteroid (BR) signaling converges with SUPPRESSOR OF PHYTOCHROME B4-#3 (SOB3) to influence both the transcription of genes involved in cell elongation and hypocotyl growth. Specifically, SOB3 mutant hypocotyl phenotypes, which are readily apparent when the seedlings are grown in dim white light, were attenuated by treatment with either brassinolide (BL) or the BR biosynthesis inhibitor brassinazole (BRZ). Hypocotyls of SOB3 mutant seedlings grown in white light with a higher fluence rate also exhibited altered sensitivities to BL, further suggesting a connection to BR signaling. However, the impact of BL treatment on SOB3 mutants grown in moderate-intensity white light was reduced when polar auxin transport was inhibited. BL treatment enhanced transcript accumulation for all six members of the SMALL AUXIN UP RNA19 (SAUR19) subfamily, which promote cell expansion, are repressed by SOB3 and light, and are induced by auxin. Conversely, BRZ inhibited the expression of SAUR19 and its homologs. Expression of these SAURs was also enhanced in lines expressing a constitutively active form of the BR signaling component BZR1, further indicating that the transcription of SAUR19 subfamily members are influenced by this hormone signaling pathway. Taken together, these results indicate that SOB3 and BR signaling converge to influence the transcription of hypocotyl growth-promoting SAUR19 subfamily members.

SUPPRESSOR OF PHYTOCHROME B4-#3 Represses Genes Associated with Auxin Signaling to Modulate Hypocotyl Growth.

Developing seedlings are well equipped to alter their growth in response to external factors in order to maximize their chances of survival. SUPPRESSOR OF PHYTOCHROME B4-#3 (SOB3) and other members of the AT-HOOK MOTIF CONTAINING NUCLEAR LOCALIZED (AHL) family of transcription factors modulate the development of Arabidopsis (Arabidopsis thaliana) by repressing hypocotyl elongation in young seedlings growing in light. However, the molecular mechanism behind how AHLs influence seedling development is largely unknown. We have identified genes associated with auxin-mediated hypocotyl elongation as downstream targets of SOB3. We found that YUCCA8 (YUC8) as well as members of the SMALL AUXIN UP-REGULATED RNA19 (SAUR19) subfamily were down-regulated in the short-hypocotyl, gain-of-function SOB3-D mutant and up-regulated in the dominant-negative, tall-hypocotyl sob3-6 mutant. SOB3-D and sob3-6 hypocotyls also exhibited altered sensitivity to the polar auxin transport inhibitor N-1-napthylphthalamic acid, suggesting a critical connection between auxin and the modulation of seedling elongation by SOB3 Finally, we found that overexpression of GREEN FLUORESCENT PROTEIN-SAUR19 in the SOB3-D line partially rescued defects in hypocotyl elongation, and SOB3 bound directly to the promoters of YUC8 and SAUR19 subfamily members. Taken together, these data indicate that SOB3 modulates hypocotyl elongation in young seedlings by directly repressing the transcription of genes associated with auxin signaling.

Impact of dexmedetomidine on early extubation in pediatric cardiac surgical patients.

PURPOSE: To evaluate the impact of dexmedetomidine on early extubation in post-operative pediatric cardiac patients compared to patients on standard sedation regimens without dexmedetomidine. METHODS: Retrospective study comparing dexmedetomidine infusion (DEX) to our standard sedation regimens (control). RESULTS: A total of 269 patients were included (control: n = 180; DEX: n = 89). The mean duration of DEX was 34 ± 2 h. Extubation was achieved in the operating room in 42% of the control group and 42% of the DEX group. Extubation within 24 h of surgery was achieved in 75% of the control group and 76% of the DEX group. Ventilator time in the DEX group was 35 ± 29 h compared to 29 ± 35 h in the control group. The mean cardiovascular intensive care unit (CV ICU) and hospital length of stays were 3 ± 2 and 8 ± 4 days in the DEX group and 3 ± 3 and 8 ± 5 days in the control group. Reintubation rates in the CV ICU were not significantly different. DEX patients received significantly less total intraoperative fentanyl and midazolam but significantly more midazolam rescue doses than the control group in the postoperative period. Post-extubation ventilation was clinically similar in the DEX group as measured by 1 h post-extubation PaCO2 levels. CONCLUSIONS: Dexmedetomidine did not significantly impact the postoperative course of children compared to standard practice as measured by success of early extubation, ventilator time, and length of stay.