PERK inhibition in zebrafish mimics human Wolcott-Rallison syndrome phenotypes.

Wolcott-Rallison Syndrome (WRS) is the most common cause of permanent neonatal diabetes mellitus among consanguineous families. The diabetes associated with WRS is non-autoimmune, insulin-requiring and associated with skeletal dysplasia and growth retardation. The therapeutic options for WRS patients rely on permanent insulin pumping or on invasive transplants of liver and pancreas. WRS has a well identified genetic cause: loss-of-function mutations in the gene coding for an endoplasmic reticulum kinase named PERK (protein kinase R-like ER kinase). Currently, WRS research is facilitated by cellular and rodent models with PERK ablation. While these models have unique strengths, cellular models incompletely replicate the organ/system-level complexity of WRS, and rodents have limited scalability for efficiently screening potential therapeutics. To address these challenges, we developed a new in vivo model of WRS by pharmacologically inhibiting PERK in zebrafish. This small vertebrate displays high fecundity, rapid development of organ systems and is amenable to highly efficient in vivo drug testing. PERK inhibition in zebrafish produced typical WRS phenotypes such as glucose dysregulation, skeletal defects, and impaired development. PERK inhibition in zebrafish also produced broad-spectrum WRS phenotypes such as impaired neuromuscular function, compromised cardiac function and muscular integrity. These results show that zebrafish holds potential as a versatile model to study WRS mechanisms and contribute to the identification of promising therapeutic options for WRS.

The Performance of Using the Parasympathetic Tone Activity (PTA) Index to Assess Intraoperative Nociception in Cats.

BACKGROUND: The monitoring of nociception/antinociception poses a significant challenge during anesthesia, making the incorporation of new tools like the Parasympathetic Tone Activity (PTA) monitor an added value in feline anesthesia. OBJECTIVES: To compare the effectiveness and speed of PTA monitoring when compared to heart rate (HR) in detecting surgical stimuli (SS) during the intraoperative period in 49 female cats undergoing ovariectomy (OV). METHODS: Instantaneous Parasympathetic Tone Activity (PTAi) values, HR, fR, and non-invasive SAP and MAP were continuously monitored and systematically assessed. The time required for HR (HR time) and PTAi (PTAi time) to reach their minimum peak values following each surgical stimulus was collected at five points for each anaesthetized cat. Each collected surgical stimulus was categorized into 3 groups for statistical analysis: no nociception detection, no hemodynamic reaction and a PTAi > 50 (Nhre); no hemodynamic reaction and a PTAi < 50 (Nhre < 50); and hemodynamic reaction and PTAi < 50 (Hre < 50). RESULTS: PTAi response demonstrated effectiveness in detecting nociception compared to HR. The SS were categorized as 36.1% in the Nhre group, 50% in the Nhre < 50 group, and only 13.9% in the Hre < 50 group. In the Hre < 50 group, PTAi time and HR time had similar speeds in detecting the SS (p = 0.821); however, PTA time was significantly slower in the Nhre < 50 group when compared to the Hre < 50 group (p = 0.001). CONCLUSIONS: PTA monitoring may be a useful tool to complement HR monitoring for detecting nociception. PTA monitoring demonstrated a superior diagnostic value compared to HR for detecting nociception in cats undergoing OV and a similar speed to HR in detecting SS when HR increases above 20%. Future studies are needed to understand in a clinical setting the meaning of sympathetic activation/nociception detected using the PTA monitor when the HR increase is not clinically relevant.

Correction to "New Pathway for Cisplatin Prodrug to Utilize Metabolic Substrate Preference to Overcome Cancer Intrinsic Resistance".

[This corrects the article DOI: 10.1021/acscentsci.3c00286.].

New Pathway for Cisplatin Prodrug to Utilize Metabolic Substrate Preference to Overcome Cancer Intrinsic Resistance.

Tumor cells adapt to diverse survival strategies defying our pursuit of multimodal cancer therapy. Prostate cancer (PCa) is an example that is resistant to one of the most potent chemotherapeutics, cisplatin. PCa cells survive and proliferate using fatty acid oxidation (FAO), and the dependence on fat utilization increases as the disease progresses toward a resistant form. Using a pool of patient biopsies, we validated the expression of a key enzyme carnitine palmitoyltransferase 1 A (CPT1A) needed for fat metabolism. We then discovered that a cisplatin prodrug, Platin-L, can inhibit the FAO of PCa cells by interacting with CPT1A. Synthesizing additional cisplatin-based prodrugs, we documented that the presence of an available carboxylic acid group near the long chain fatty acid linker on the Pt(IV) center is crucial for CPT1A binding. As a result of fat metabolism disruption by Platin-L, PCa cells transition to an adaptive glucose-dependent chemosensitive state. Potential clinical translation of Platin-L will require a delivery vehicle to direct it to the prostate tumor microenvironment. Thus, we incorporated Platin-L in a biodegradable prostate tumor-targeted orally administrable nanoformulation and demonstrated its safety and efficacy. The distinctive FAO inhibitory property of Platin-L can be of potential clinical relevance as it offers the use of cisplatin for otherwise resistant cancer.

Alternativas tecnológicas ao jateamento de areia seca: a busca da incorporaçäo de novos elementos na avaliaçäo das exposiçöes / Technological alternatives to the jet of sand evaporate: the search of the incorporation of new elements in the evaluation of the exhibitions

Compreende a dinâmica da relaçao entre processo de trabalho e saúde como um dos determinantes do processo saúde-doença. Através de um estudo de caso, é discutido o processo de vigilância em saúde do trabalhador na indústria naval no Estado do Rio de Janeiro desenvolvido no período compreendido entre 1989 e 1996, a partir de recorte da implementaçao das alternativas tecnológicas ao jateamento de areia seca. Tem como referência o método de investigaçao através de aproximaçoes sucessivas utilizado na Vigilância em Saúde do Trabalhador pelo Programa de Saúde do Trabalhador (PST/SES-RJ), onde têm destaque os pressupostos da participaçao dos trabalhadores e da interdisciplinaridade. Discute os resultados das investigaçoes acerca dos diferentes métodos abrasivos e a heterogeneidade do processo de trabalho na indústria naval, onde a organizaçao do trabalho determina formas heterogêneas de exposiçao que, por sua vez, têm se refletido no caráter diferenciado da contaminaçao dos trabalhadores. A constataçao da grande variabilidade nos resultados das avaliaçoes de exposiçao dos trabalhadores e da impossibilidade de estabelecer com precisao grupos de risco demonstrou a complexidade do monitoramento e da avaliaçao das alternativas tecnológicas introduzidas com a proibiçao do jateamento com areia seca. A partir da sistematizaçao das informaçoes e dos viabilizados pelo processo de vigilância, busca contribuir para a incorporaçao de elementos qualitativos na análise do processo de trabalho e na avaliaçao das exposiçoes a que os trabalhadores sao submetidos.