Optimizing Arsenic Therapy by Selectively Targeting Leukemia Cells.

Arsenic, in the simple form of arsenic trioxide, is currently marketed for the treatment of acute promyelocytic leukemia. Due to the multifaceted mechanisms of action of arsenic, it has also shown promise in other types of leukemias but is hindered by its toxic effects toward normal cells. This research has aimed to determine whether tumor-homing peptide complexes of arsenic can be designed and developed to strategically target specific cancers. The end goal is to achieve dose reduction and decreased side effects of the resultant arsenic therapeutic agent. In this article, we present the synthesis, characterization, and stability studies of a new class of As-peptide complexes designed to target leukemia. In vitro biological studies of the most stable complex show 1000 times greater toxicity toward leukemia cells over human blood cells, indicating potential for progression to in vivo studies.

Anesthetic choice for arteriovenous access creation: A National Anesthesia Clinical Outcomes Registry analysis.

BACKGROUND: We sought to evaluate differences in primary anesthetic type used in arteriovenous access creation with the hypothesis that administration of regional anesthesia and monitored anesthesia care (MAC) with local anesthesia as the primary anesthetic has increased over time. METHODS: National Anesthesia Clinical Outcomes Registry data were retrospectively evaluated. Covariates were selected a priori within multivariate models to determine predictors of anesthetic type in adults who underwent elective arteriovenous access creation between 2010 and 2018. RESULTS: A total of 144,392 patients met criteria; 90,741 (62.8%) received general anesthesia. The use of regional anesthesia and MAC decreased over time (8.0%-6.8%, 36.8%-27.8%, respectively; both p < 0.0001). Patients who underwent regional anesthesia were more likely to have ASA physical status >III and to reside in rural areas (52.3% and 12.9%, respectively; both p < 0.0001). Patients who underwent MAC were more likely to be older, male, receive care outside the South, and reside in urban areas (median age 65, 56.8%, 68.1%, and 70.8%, respectively; all p < 0.0001). Multivariate analysis revealed that being male, having an ASA physical status >III, and each 5-year increase in age resulted in increased odds of receiving alternatives to general anesthesia (regional anesthesia adjusted odds ratios (AORs) 1.06, 1.12, and 1.26, MAC AORs 1.09, 1.2, and 1.1, respectively; all p < 0.0001). Treatment in the Midwest, South, or West was associated with decreased odds of receiving alternatives to general anesthesia compared to the Northeast (regional anesthesia AORs 0.28, 0.38, and 0.03, all p < 0.0001; MAC 0.76, 0.13, and 0.43, respectively; all p < 0.05). CONCLUSIONS: Use of regional anesthesia and MAC with local anesthesia for arteriovenous access creation has decreased over time with general anesthesia remaining the primary anesthetic type. Anesthetic choice, however, varies with patient characteristics and geography.

Mutagenesis of the cleavage site of (pro)renin receptor abrogates aldosterone-salt-induced hypertension and renal injury in mice.

Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease and furin. It has been reported that sPRR functions as an important regulator of intrarenal renin contributing to angiotensin II (ANG II)-induced hypertension. Relatively, less is known for the function of sPRR in ANG II-independent hypertension such as mineralocorticoid excess. In the present study, we used a novel mouse model with mutagenesis of the cleavage site in PRR (termed as PRRR279V/L282V or mutant) to examine the phenotype during aldosterone (Aldo)-salt treatment. The hypertensive response of mutant mice to Aldo-salt treatment was blunted in parallel with the attenuated response of plasma volume expansion and renal medullary α-epithelial Na+ channel expression. Moreover, Aldo-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied by blunted polydipsia and polyuria. Together, these results represent strong evidence favoring endogenous sPRR as a mediator of Aldo-salt-induced hypertension and renal injury.NEW & NOTEWORTHY We used a novel mouse model with mutagenesis of the cleavage site of PRR to support soluble PRR as an essential mediator of aldosterone-salt-induced hypertension and also as a potential therapeutic target for patients with mineralocorticoid excess. We firstly report that soluble PRR-dependent pathway medicates the Na+-retaining action of aldosterone in the distal nephron, which opens up a new area for a better understanding of the molecular basis of renal handling of Na+ balance and blood pressure.

Single-Shot Intrinsic Calibration for Autonomous Driving Applications.

In this paper, we present a first-of-its-kind method to determine clear and repeatable guidelines for single-shot camera intrinsic calibration using multiple checkerboards. With the help of a simulator, we found the position and rotation intervals that allow optimal corner detector performance. With these intervals defined, we generated thousands of multiple checkerboard poses and evaluated them using ground truth values, in order to obtain configurations that lead to accurate camera intrinsic parameters. We used these results to define guidelines to create multiple checkerboard setups. We tested and verified the robustness of the guidelines in the simulator, and additionally in the real world with cameras with different focal lengths and distortion profiles, which help generalize our findings. Finally, we used a 3D LiDAR (Light Detection and Ranging) to project and confirm the quality of the intrinsic parameters projection. We found it possible to obtain accurate intrinsic parameters for 3D applications, with at least seven checkerboard setups in a single image that follow our positioning guidelines.

Successful treatment of intravenous drug abuser with refractory vasoplegic syndrome after mitral valve repair for infective endocarditis.

Vasoplegic syndrome, a possible complication of cardiopulmonary bypass, is a critical state of unregulated systemic vasodilation with decreased vascular resistance and a pathological insensitivity to conventional inotropes and vasoconstrictors. This case demonstrates the use of methylene blue and hydroxocobalamin as medications in the treatment of refractory vasoplegic syndrome in the context of cardiac surgery due to their differences in mechanism of action. A 24-year-old female with history of intravenous drug abuse and hepatitis C infection underwent mitral valve repair for infective endocarditis. Preoperative transesophageal echocardiography showed normal right ventricular function, left ventricular ejection fraction of 65%-75%, and severe mitral regurgitation with vegetation. In order to maintain a mean arterial pressure over 60 mmHg during cardiopulmonary bypass, norepinephrine, epinephrine, and vasopressin infusions were required. Given the patient's minimal response to these medications, a 1.5 mg/kg bolus of intravenous methylene blue was also given intraoperatively; vasoplegic syndrome remained refractory in the post-cardiopulmonary bypass period. A 5 g dose of intravenous hydroxocobalamin was administered in the intensive care unit postoperatively. Postoperative liver function tests were abnormal, and post-cardiopulmonary bypass transesophageal echocardiography revealed mildly decreased right ventricular function. While in the intensive care unit, the patient was placed on venoarterial extracorporeal membrane oxygenation and underwent therapeutic plasma exchange. Vasopressors were weaned over the course of the next 24 h. The patient was able to be transferred out of the intensive care unit on postoperative day 5. Traditional vasoconstrictors activate signal transduction pathways that lead to myosin phosphorylation. Vasodilatory molecules such as nitric oxide (NO) activate the enzyme soluble guanylyl cyclase (sGC), ultimately leading to the dephosphorylation of myosin. Nitric Oxide Synthase (NOS) can potentially increase NO levels 1000-fold when activated by inflammatory cytokines. Methylene blue is a direct inhibitor of NOS. It also binds and inhibits sGC. Hydroxocobalamin is a direct inhibitor of NO, likely inhibits NOS and may also act through additional mechanisms.

Alkaloids from the root of Indonesian Annona muricata L.

Annona muricata L. has been used traditionally in Indonesia to treat disease. Phytochemical studies on the alkaloid fractions from the root of Annona muricata L. from Malang-Indonesia resulted in the isolation of an unreported benzylisoquinoline alkaloid (+)-xylopine 5 as well as four known alkaloids (1-4). The crude methanol extract and alkaloid fractions were tested against Plasmodium falciparum K1 and against bacteria (Escherichia coli, Klebsiella pneumonia, Acinetobacter buamanii, Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus) with insignificant activities (MIC > 32 µg/mL). Individual alkaloids were tested against a human suspension cancer cell line (HL-60 leukemia cells) and two human fibroblastic cancer cell lines (A549 lung cancer cells and HepG2 liver cancer cells) in which compound 5 was the most toxic alkaloid with IC50 values ranging from 20 to 80 µM.

Anti-cancer Evaluation of Depsides Isolated from Indonesian Folious Lichens: Physcia millegrana, Parmelia dilatata and Parmelia aurulenta.

Cancer is a serious health burden on global societies. The discovery and development of new anti-cancer therapies remains a challenging objective. Although it has been shown that lichen secondary metabolites may be potent sources for new anti-cancer agents, the Indonesian- grown folious lichens, Physcia millegrana,Parmelia dilatata and Parmeila aurulenta, have not yet been explored. In this study exhaustive preparative high-performance liquid chromatography was employed to isolate the lichen constituents with spectroscopic and spectrometric protocols identifying nine depsides 9-17, including the new methyl 4-formyl-2,3-dihydroxy-6-methylbenzoate 13. The cytotoxicity of the depsides towards cancer cells was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results indicated lowest toxicity of the depsides towards human A549 lung cancer cells. Importantly, the di-depsides (11, 12 and 17) showed greatest toxicity, indicating that these structures are biologically more active than the mono-depsides against the HepG2 liver cancer, A549 lung cancer and HL-60 leukemia cell lines.