Intraoperative vasopressor use and early postoperative acute kidney injury in elderly patients undergoing elective noncardiac surgery.

BACKGROUND: Intraoperative hypotension is a risk factor for postoperative acute kidney injury (AKI). Elderly patients are susceptible due to reduced responses to acute hemodynamic changes. AIMS: Determine the association between hypotension identified from anesthetic charts and postoperative AKI in elderly patients. METHODS: Retrospective cohort study of elective noncardiac surgery patients ≥65 years, at an Australian tertiary hospital (December 2019-March 2021), with the primary outcome of AKI ≤48 h of surgery. Factors of interest were intraoperative hypotension determined from anesthetic charts (mean arterial pressure <60 mmHg, systolic blood pressure <90 mmHg, recorded 5-min) and intraoperative vasopressor use. RESULTS: In 830 patients (mean age 75 years), systolic hypotension was more frequent than mean arterial hypotension (25.7% vs. 11.9%). Most hypotensive episodes were brief (7.2% of systolic and 4.2% of mean arterial hypotension lasted >10 min) but vasopressors were used in 84.7% of cases. The incidence of postoperative AKI was 13.9%. Systolic hypotension >20 min was associated with AKI (OR, 3.88; 95% CI: 1.38-10.9), which was not significant after adjusting for vasopressors, creatinine, American Society of Anesthesiologists class, and hemoglobin drop. The cumulative dose of any specific vasopressor >20 mg (or >10 mg epinephrine) was independently associated with AKI (adjusted OR, 2.47; 95% CI: 1.34-4.58). Every 5 mg increase in the total dose of all intraoperative vasopressors used during surgery was associated with 11% increased odds of AKI (95% CI: 3-19%). CONCLUSIONS: High vasopressor use was associated with postoperative AKI in elderly patients undergoing noncardiac surgery, independent of hypotension identified from anesthetic charts.

Dual-Modality PET-SPECT Image-Guided Pretargeting Delivery in HER2(+) Breast Cancer Models.

Pretargeted drug delivery has been explored for decades as a promising approach in cancer therapy. An image-guided pretargeting strategy significantly enhances the intrinsic advantages of this approach since imaging the pretargeting step can be used for diagnostic purposes, while imaging of the drug delivery step can be utilized to evaluate drug distribution and assess therapeutic response. A trastuzumab (Tz)-based HER2 pretargeting component (Tz-TCO-[89Zr-DFO]) was developed by conjugating with trans-cyclooctene (TCO) bioorthogonal click chemistry functional groups and deferoxamine (DFO) to enable radiolabeling with a 89Zr PET tracer. The drug delivery component (HSA-DM1-Tt-[99mTc-HyNic]) was developed by conjugating human serum albumin (HSA) with mertansine (DM1), tetrazine (Tt) functional groups, and a HyNic chelator and radiolabeling with 99mTc. For ex vivo biodistribution studies, pretargeting and delivery components (without drug) were administered subsequently to mice bearing human HER2(+) breast cancer xenografts, and a high tumor uptake of Tz-TCO-[89Zr-DFO] (26.4% ID/g) and HSA-Tt-[99mTc-HyNic] (4.6% ID/g) was detected at 24 h postinjection. In vivo treatment studies were performed in the same HER2(+) breast cancer model using PET-SPECT image guidance. The increased tumor uptake of the pretargeting and drug delivery components was detected by PET-CT and SPECT-CT, respectively. The study showed a significant 92% reduction of the relative tumor volume in treated mice (RTV = 0.08 in 26 days), compared to the untreated control mice (RTV = 1.78 in 11 days) and to mice treated with only HSA-DM1-Tt-[99mTc-HyNic] (RTV = 1.88 in 16 days). Multimodality PET-SPECT image-guided and pretargeted drug delivery can be utilized to maximize efficacy, predict therapeutic response, and minimize systemic toxicity.

Development of 5D3-DM1: A Novel Anti-Prostate-Specific Membrane Antigen Antibody-Drug Conjugate for PSMA-Positive Prostate Cancer Therapy.

Prostate cancer (PC) is a potentially high-risk disease and the most common cancer in American men. It is a leading cause of cancer-related deaths in men in the US, second only to lung and bronchus cancer. Advanced and metastatic PC is initially treated with androgen deprivation therapy (ADT), but nearly all cases eventually progress to castrate-resistant prostate cancer (CRPC). CRPC is incurable in the metastatic stage but can be slowed by some conventional chemotherapeutics and second-generation ADT, such as enzalutamide and abiraterone. Therefore, novel therapeutic strategies are urgently needed. Prostate-specific membrane antigen (PSMA) is overexpressed in almost all aggressive PCs. PSMA is widely used as a target for PC imaging and drug delivery. Anti-PSMA monoclonal antibodies (mAbs) have been developed as bioligands for diagnostic imaging and targeted PC therapy. However, these mAbs are successfully used in PC imaging and only a few have gone beyond phase-I for targeted therapy. The 5D3 mAb is a novel, high-affinity, and fast-internalizing anti-PSMA antibody. Importantly, 5D3 mAb demonstrates a unique pattern of cellular localization to the centrosome after internalization in PSMA(+) PC3-PIP cells. These characteristics make 5D3 mAb an ideal bioligand to deliver tubulin inhibitors, such as mertansine, to the cell centrosome, leading to mitotic arrest and elimination of dividing PC cells. We have successfully developed a 5D3 mAb- and mertansine (DM1)-based antibody-drug conjugate (ADC) and evaluated it in vitro for binding affinity, internalization, and cytotoxicity. The in vivo therapeutic efficacy of 5D3-DM1 ADC was evaluated in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu mouse models of human PC. This therapeutic study has revealed that this new anti-PSMA ADC can successfully control the growth of PSMA(+) tumors without inducing systemic toxicity.

Cellular Delivery of Bioorthogonal Pretargeting Therapeutics in PSMA-Positive Prostate Cancer.

Prostate cancer is primarily fatal after it becomes metastatic and castration-resistant despite novel combined hormonal and chemotherapeutic regimens. Hence, new therapeutic concepts and drug delivery strategies are urgently needed for the eradication of this devastating disease. Here we report the highly specific, in situ click chemistry driven pretargeted delivery of cytotoxic drug carriers to PSMA(+) prostate cancer cells. Anti-PSMA 5D3 mAb and its F(ab')2 fragments were functionalized with trans-cyclooctene (TCO), labeled with a fluorophore, and used as pretargeting components. Human serum albumin (ALB) was loaded with the DM1 antitubulin agent, functionalized with PEGylated tetrazine (PEG4-Tz), labeled with a fluorophore, and used as the drug delivery component. The internalization kinetics of components and the therapeutic efficacy of the pretargeted click therapy were studied in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu control cells. The F(ab')2 fragments were internalized faster than 5D3 mAb in PSMA(+) PC3-PIP cells. In the two-component pretargeted imaging study, both components were colocalized in a perinuclear location of the cytoplasm of PC3-PIP cells. Better colocalization was achieved when 5D3 mAb was used as the pretargeting component. Consecutively, the in vitro cell viability study shows a significantly higher therapeutic effect of click therapy in PC3-PIP cells when 5D3 mAb was used for pretargeting, compared to its F(ab')2 derivative. 5D3 mAb has a longer lifetime on the cell surface, when compared to its F(ab')2 analogue, enabling efficient cross-linking with the drug delivery component and increased efficacy. Pretargeting and drug delivery components were cross-linked via multiple bioorthogonal click chemistry reactions on the surface of PSMA(+) PC cells forming nanoclusters, which undergo fast cellular internalization and intracellular transport to perinuclear locations.

Simple model for orthogonal and angled coupling in dielectric-plasmonic waveguides.

We numerically and analytically study orthogonal and angled coupling schemes between a dielectric slab waveguide and a plasmonic slot waveguide for a large range of geometric and material parameters. We obtain high orthogonal coupling transmission efficiencies (up to 78% for 2D calculations, and 54% for 3D calculations) over a wide range of refractive indices, and provide simple analytic arguments that explain the underlying trends. The insights obtained point to angled couplers with even higher coupling efficiencies (up to 86% in 2D, and 61% in 3D). We find that angled plasmonic coupling is well suited for large dielectric waveguides at the phase matching angle. These results suggest new capabilities for efficient dielectric-plasmonic interconnects that can be applied to a wide variety of material combinations and geometries.

Insight meditation and telomere biology: The effects of intensive retreat and the moderating role of personality.

A growing body of evidence suggests that meditation training may have a range of salubrious effects, including improved telomere regulation. Telomeres and the enzyme telomerase interact with a variety of molecular components to regulate cell-cycle signaling cascades, and are implicated in pathways linking psychological stress to disease. We investigated the effects of intensive meditation practice on these biomarkers by measuring changes in telomere length (TL), telomerase activity (TA), and telomere-related gene (TRG) expression during a 1-month residential Insight meditation retreat. Multilevel analyses revealed an apparent TL increase in the retreat group, compared to a group of experienced meditators, similarly comprised in age and gender, who were not on retreat. Moreover, personality traits predicted changes in TL, such that retreat participants highest in neuroticism and lowest in agreeableness demonstrated the greatest increases in TL. Changes observed in TRGs further suggest retreat-related improvements in telomere maintenance, including increases in Gar1 and HnRNPA1, which encode proteins that bind telomerase RNA and telomeric DNA. Although no group-level changes were observed in TA, retreat participants' TA levels at post-assessment were inversely related to several indices of retreat engagement and prior meditation experience. Neuroticism also predicted variation in TA across retreat. These findings suggest that meditation training in a retreat setting may have positive effects on telomere regulation, which are moderated by individual differences in personality and meditation experience. (ClinicalTrials.gov #NCT03056105).

Experimental investigation of the frequency dependence of the electrorheological effect.

The frequency dependence of the electrorheological response was studied experimentally in a suspension of barium titanate spherical particles suspending in silicone oil. In the system, only one factor, namely the frequency of the applied electric field, affects the electrorheological effect. The experimental data reflect the frequency effect more reliably and more accurately. Under the sinusoidal electric fields, the shear stress increases sharply with frequency below 500 Hz and reaches a saturated value beyond 500 Hz. The phenomena can be explained well with the permittivity mismatch theory. More experiments indicate that the electrorheological effect should be the sum of the mismatch polarization and the interfacial polarization.