De Novo and Histologically Transformed Small-Cell Lung Cancer Is Sensitive to Lurbinectedin Treatment Through the Modulation of EMT and NOTCH Signaling Pathways.

PURPOSE: Small-cell lung cancer (SCLC) is a high-grade neuroendocrine tumor with dismal prognosis and limited treatment options. Lurbinectedin, conditionally approved as a second-line treatment for metastatic SCLC, drives clinical responses in about 35% of patients, and the overall survival (OS) of those who benefit from it remains very low (∼9.3 months). This finding highlights the need to develop improved mechanistic insight and predictive biomarkers of response. EXPERIMENTAL DESIGN: We used human and patient-derived xenograft (PDX)-derived SCLC cell lines to evaluate the effect of lurbinectedin in vitro. We also demonstrate the antitumor effect of lurbinectedin in multiple de novo and transformed SCLC PDX models. Changes in gene and protein expression pre- and post-lurbinectedin treatment was assessed by RNA sequencing and Western blot analysis. RESULTS: Lurbinectedin markedly reduced cell viability in the majority of SCLC models with the best response on POU2F3-driven SCLC cells. We further demonstrate that lurbinectedin, either as a single agent or in combination with osimertinib, causes an appreciable antitumor response in multiple models of EGFR-mutant lung adenocarcinoma with histologic transformation to SCLC. Transcriptomic analysis identified induction of apoptosis, repression of epithelial-mesenchymal transition, modulation of PI3K/AKT, NOTCH signaling associated with lurbinectedin response in de novo, and transformed SCLC models. CONCLUSIONS: Our study provides a mechanistic insight into lurbinectedin response in SCLC and the first demonstration that lurbinectedin is a potential therapeutic target after SCLC transformation.

Stearoyl coenzyme A desaturase-1: multitasker in cancer, metabolism, and ferroptosis.

Cancer progression is a highly balanced process and is maintained by a sequence of finely tuned metabolic pathways. Stearoyl coenzyme A desaturase-1 (SCD1), the fatty enzyme that converts saturated fatty acids into monounsaturated fatty acids, is a critical modulator of the fatty acid metabolic pathway. SCD1 expression is associated with poor prognosis in several cancer types. SCD1 triggers an iron-dependent cell death called ferroptosis and elevated levels of SCD1 protect cancer cells against ferroptosis. Pharmacological inhibition of SCD1 as monotherapy and in combination with chemotherapeutic agents shows promising antitumor potential in preclinical models. In this review, we summarize the role of SCD in cancer cell progression, survival, and ferroptosis and discuss potential strategies to exploit SCD1 inhibition in future clinical trials.

Proton nuclear magnetic resonance (1H NMR) of flammable organic chemicals in radioactive high-level supernatant waste at the Savannah River Site (SRS).

The Savannah River Site stores approximately 36 million gallons of radioactive and hazardous waste that contains approximately 245 million curies. The waste is sent through various chemical processes to reduce its volume and to separate various components. The facility plans to replace formic acid (a chemical used to reduce soluble mercury) with glycolic acid. Recycle solution with glycolate may flow back to the tank farm, where the glycolate can generate hydrogen gas by thermal and radiolytic mechanisms. The current analytical method for detecting glycolate (ion chromatography) in supernatant requires a large dilution to reduce interference from the nitrate anions. Hydrogen nuclear magnetic resonance is an analytical method that requires less sample dilution. It takes advantage of the CH2 group in glycolate. Liquid samples were spiked with four different levels of glycolate to build a calibration line, as it is recommended in the standard addition method. The detection and quantitation limits determined were 1 and 5 ppm, respectively, for 32 scans, which is well below the process limit of 10 ppm. In one test, 800 scans of a supernatant spiked with 1 ppm glycolate resulted in a -CH2 peak with a signal-to-noise ratio of 36.

A new species of Ampithoe (Amphipoda, Ampithoidae) from Korea, with a redescription of A.tarasovi.

An ampithoid species, previously known as A.tarasovi in Korea, is assigned as a new species, A.changbaensis sp. nov. based on the reexamination of the holotype of A.tarasovi. The new species shows different morphological characteristics compared to A.tarasovi, especially in male gnathopods 1 and 2. The type material of A.tarasovi is redescribed and illustrated here and a key to the Korean species of Ampithoe is provided.

Real time monitoring of oxygen uptake of hepatocytes in a microreactor using optical microsensors.

Most in vitro test systems for the assessment of toxicity are based on endpoint measurements and cannot contribute much to the establishment of mechanistic models, which are crucially important for further progress in this field. Hence, in recent years, much effort has been put into the development of methods that generate kinetic data. Real time measurements of the metabolic activity of cells based on the use of oxygen sensitive microsensor beads have been shown to provide access to the mode of action of compounds in hepatocytes. However, for fully exploiting this approach a detailed knowledge of the microenvironment of the cells is required. In this work, we investigate the cellular behaviour of three types of hepatocytes, HepG2 cells, HepG2-3A4 cells and primary mouse hepatocytes, towards their exposure to acetaminophen when the availability of oxygen for the cell is systematically varied. We show that the relative emergence of two modes of action, one NAPQI dependent and the other one transient and NAPQI independent, scale with expression level of CYP3A4. The transient cellular response associated to mitochondrial respiration is used to characterise the influence of the initial oxygen concentration in the wells before exposure to acetaminophen on the cell behaviour. A simple model is presented to describe the behaviour of the cells in this scenario. It demonstrates the level of control over the role of oxygen supply in these experiments. This is crucial for establishing this approach into a reliable and powerful method for the assessment of toxicity.

Taxonomic study on the photid amphipods (Senticaudata, Corophiida, Photoidea, Photidae) from Korean waters, with descriptions of a new genus and seven new species.

In this paper, seven new species of the family Photidae from Korean waters are described and illustrated in detail. Among them, Exiliphotis petila sp. nov. is a monotype of the newly reported Exiliphotis gen. nov., which is characterized by slenderer and more elongate pereopods 5-7 than those of other genera of the family Photidae. The genus Latigammaropsis is reported for the first time from Korean waters based on the description of Latigammaropsis careocavata sp. nov., which is differentiated from other Gammaropsis group by having weakly sexual dimorphic gnathopods 2, those have simple palmar margins in both sexes. Three new species of Photis are also described: Photis bronca sp. nov., Photis posterolobus sp. nov., and Photis longicarpus sp. nov. The formerly misidentified Photis longicaudata from Japan and China as well as the Korean material could be classified as a new species, P. bronca sp. nov. For that, the syntypes of P. longicaudata were re-examined, and lectotype and paralectotypes were newly designated in this study. Photis bronca sp. nov. is characterized by quadrate tooth on the palmar margin medially on gnathopod 2 in both sexes. Photis posterolobus sp. nov. shows a pointed posterior lobe on the ischium and a well-developed process of the propodus on male gnathopod 2. Photis longicarpus sp. nov. can be distinguished from other species of the genus by very elongate carpus of male gnathopod 1. Two new species belonging to the genus Podoceropsis are also reported: Podoceropsis insinuomanus sp. nov. has a strongly bisinuous palmar margin on male gnathopod 2, and Podoceropsis pseudoclavapes sp. nov. differs from the closely related species of Podoceropsis clavapes by different shape of the palmar margin and shorter dactylus of male gnathopod 2. Additionally, a key to the Korean species of Photidae is provided.

Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model.

In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E2 (PGE2), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE2 synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE2 concentration that was completely abrogated in mPGES-1-deficient mice. PGE2 is known to inhibit TNF-α synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-α expression. Due to the impaired PGE2 production, TNF-α expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-α resulted in an enhanced IL-1ß production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE2 production by mPGES-1 ablation enhanced the TNF-α-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.

Amphipod family distributions around Iceland.

Amphipod crustaceans were collected at all 55 stations sampled with an epibenthic sledge during two IceAGE expeditions (Icelandic marine Animals: Genetics and Ecology) in 2011 and 2013. In total, 34 amphipod families and three superfamilies were recorded in the samples. Distribution maps are presented for each taxon along with a summary of the regional taxonomy for the group. Statistical analyses based on presence/absence data revealed a pattern of family distributions that correlated with sampling depth. Clustering according to the geographic location of the stations (northernmost North Atlantic Sea and Arctic Ocean) can also be observed. IceAGE data for the Amphilochidae and Oedicerotidae were analysed on species level; in case of the Amphilochidae they were compared to the findings from a previous Icelandic benthic survey, BIOICE (Benthic Invertebrates of Icelandic waters), which also identified a high abundance of amphipod fauna.

First records of the uristid lysianassoids from Korean waters: redescription of Anonyx abei Takekawa & Ishimaru, 2001 and description of Anonyx exilipes sp. n. (Crustacea, Amphipoda, Uristidae).

The uristid lysianassoids are reported for the first time from Korean waters with a redescription of Anonyx abei Takekawa & Ishimaru, 2001 and the description of Anonyx exilipessp. n.Anonyx abei is characterized by a distinctively small projection of the posterodistal corner on epimeron 3, different from all species of the Anonyx nugax group which share a constriction at the point of insertion of a distal seta on the inner ramus of uropod 2. Anonyx exilipessp. n. is included in the Anonyx laticoxae group characterized by the unconstricted inner ramus of uropod 2. This new species is distinguished from other A. laticoxae group species by the longer and more slender carpus and propodus of pereopod 6, and the non-lobate merus of pereopod 7.

Aroui minusetosus, a new species of Scopelocheiridae from Korea (Crustacea, Amphipoda, Lysianassoidea).

A new species, Aroui minusetosussp. n., is recorded from Korean waters with detailed description and illustrations. A new key to all known Aroui is provided. The Korean material of this scopelocheirid is readily assigned to the genus Aroui by the presence of long and distally barbed setae on the outer plate of maxilla 2. This new species is distinguished from congeners by ventrally smooth coxae 1-3 and a setose posteroventral margin of coxa 4, the subchelate gnathopod 2 having a row of four robust setae on its posterior margin (including an elongate single locking seta), and the setation of all appendages which is less dense than in other species. This is the first record of scopelocheirid amphipods from Korean waters.