Non-Small Cell Lung Cancer Imaging Using a Phospholipase A2 Activatable Fluorophore.

Lung cancer, the most common cause of cancer-related death in the United States, requires advanced intraoperative detection methods to improve evaluation of surgical margins. In this study we employed DDAO-arachidonate (DDAO-A), a phospholipase A2 (PLA2) activatable fluorophore, designed for the specific optical identification of lung cancers in real-time during surgery. The in vitro fluorescence activation of DDAO-A by porcine sPLA2 was tested in various liposomal formulations, with 100 nm extruded EggPC showing the best overall characteristics. Extruded EggPC liposomes containing DDAO-A were tested for their stability under various storage conditions, demonstrating excellent stability for up to 4 weeks when stored at -20 °C or below. Cell studies using KLN 205 and LLC1 lung cancer cell lines showed DDAO-A activation was proportional to cell number. DDAO-A showed preferential activation by human recombinant cPLA2, an isoform highly specific to arachidonic acid-containing lipids, when compared to a control probe, DDAO palmitate (DDAO-P). In vivo studies with DBA/2 mice bearing KLN 205 lung tumors recapitulated these results, with preferential activation of DDAO-A relative to DDAO-P following intratumoral injection. Topical application of DDAO-A-containing liposomes to human (n = 10) and canine (n = 3) lung cancers ex vivo demonstrated the preferential activation of DDAO-A in tumor tissue relative to adjacent normal lung tissue, with fluorescent tumor-to-normal ratios (TNR) of up to 5.2:1. The combined results highlight DDAO-A as a promising candidate for clinical applications, showcasing its potential utility in intraoperative and back-table imaging and topical administration during lung cancer surgeries. By addressing the challenge of residual microscopic disease at resection margins and offering stability in liposomal formulations, DDAO-A emerges as a potentially valuable tool for advancing precision lung cancer surgery and improving curative resection rates.

Cardiovascular Autonomic Deficits in Different Types of Achalasia.

Background and objective Achalasia cardia is a primary esophageal motility disorder, and the etiopathology of this disease's progression is not known. Moreover, autonomic dysfunction has not been studied in different types of achalasia. In light of this, we aimed to address this lack of data in this study. Methods The diagnosis of achalasia was done using high-resolution esophageal manometry (HRM)-based Chicago classification v4.0. Autonomic function tests (AFT) such as the head-up tilt test, deep breathing test (DBT), Valsalva maneuver (VM), handgrip test (HGT), and cold pressor test (CPT), as well as the heart rate variability (HRV) test, were performed among the cohort and the results were compared with those of 39 age- and sex-matched healthy controls. Results AFT and HRV tests were done on 62 patients (30 achalasia type I, 28 type II, and 4 type III) and compared with 39 age- and sex-matched healthy controls. The mean duration of symptoms, high Eckardt score, and dysphagia were most common in type I achalasia, followed by type II and III. The results of AFT showed a generalized loss of parasympathetic and baroreflex-independent sympathetic reactivity in all types of achalasia. However, baroreflex-dependent cardiovascular adrenergic reactivity was normal. Regarding cardiac autonomic tone, there was a loss of parasympathetic and sympathetic influence, but sympathovagal balance was maintained. The severity of the loss of autonomic functions was higher in type I, followed by type II. Conclusions In all types of achalasia, parasympathetic reactivity, baroreflex-independent sympathetic reactivity, and cardiac autonomic tone were lower compared to healthy controls, and the severity of dysfunction increased during the progression of the disease from type II to type I.

Development of 4-phenylbutyric acid microsponge gel formulations for the treatment of lewisite-mediated skin injury.

Lewisite, a chemical warfare agent, causes skin blisters, erythema, edema, and inflammation, requiring mitigation strategies in case of accidental or deliberate exposure. 4-phenyl butyric acid (4-PBA), a chemical chaperone, reduces endoplasmic reticulum stress and skin inflammation. The study aimed to encapsulate 4-PBA in microsponges for effective, sustained delivery against lewisite injury. Porous microsponges in a topical gel would potentially sustain delivery and improve residence time on the skin. Microsponges were developed using the quasi-emulsion solvent diffusion method with Eudragit RS100. Optimized formulation showed 10.58%w/w drug loading was incorporated in a carboxymethylcellulose (CMC) and Carbopol gel for in vitro release and permeation testing using dermatomed human skin. A sustained release was obtained from all vehicles in the release study, and IVPT results showed that compared to the control (41.52 ± 2.54 µg/sq.cm), a sustained permeation profile with a reduced delivery was observed for microsponges in PBS (14.16 ± 1.23 µg/sq.cm) along with Carbopol 980 gel (12.55 ± 1.41 µg/sq.cm), and CMC gel (10.09 ± 1.23 µg/sq.cm) at 24 h. Optimized formulation showed significant protection against lewisite surrogate phenyl arsine oxide (PAO) challenged skin injury in Ptch1+/-/SKH-1 hairless mice at gross and molecular levels. A reduction in Draize score by 29%, a reduction in skin bifold thickness by 8%, a significant reduction in levels of IL-1ß, IL6, and GM-CSF by 54%, 30%, and 55%, respectively, and a reduction in apoptosis by 31% was observed. Thus, the translational feasibility of 4-PBA microsponges for effective, sustained delivery against lewisite skin injury is demonstrated.

Clinical profile of central nervous system space-occupying lesions and their association with CD4 counts in patients with HIV: A prospective observational study.

Background: Neurological manifestations are one of the major concerns for patients with human immunodeficiency virus (HIV). The secondary spectrum includes space-occupying lesions (SOL), including tuberculoma, cryptococcosis, candidiasis, toxoplasmosis, primary central nervous system lymphoma (PCNSL), and progressive multifocal leukoencephalopathy (PML). Aim: To assess the neurological manifestations, disease outcome, and their associations with cluster of differentiation 4 (CD4) counts in patients with HIV. Materials and Methods: This single-center, prospective, observational study was performed in the Department of General Medicine of a tertiary care institute, over a period of 2 years (January 2017 to December 2018). The study included 150 known or newly diagnosed HIV patients with CNS SOL. The physical examination, laboratory investigations, and imaging were conducted on every patient, and the findings were noted. Results: The patients mainly presented with hemiparesis (52%), had involvement of the frontal region (38.7%), and were diagnosed with tuberculoma (29.3%). Other diagnoses were toxoplasmosis (22.7%), PML (17.3%), PCNSL (15.3%), brain abscess (10%), and neurocysticercosis (5.3%). Of 150 patients, 136 (90.7%) were survivors, while 14 (9.3%) were non-survivors. The mean CD4 count was significantly less in patients with toxoplasmosis (P < 0.0001) and PCNSL (P = 0.02), and significantly higher in patients with tuberculoma (P < 0.0001) and brain abscess (P = 0.0009) relative to other causes of SOL. Moreover, the mean CD4 count was not significantly associated with survivors and non-survivors (P = 0.28). Conclusion: In patients with HIV, CD4 count was significantly low in toxoplasmosis and PCNSL, and high in tuberculoma and brain abscess.

Differential regulation of key triterpene synthase gene under abiotic stress in Withania somnifera L. Dunal and its co-relation to sterols and withanolides.

Withania somnifera (Ashwagandha), is one of the most reputed Indian medicinal plants, having immense pharmacological activities due to the occurrence of withanolides. The withanolides are biosynthesized through triterpenoid biosynthetic pathway with the involvement of WsCAS leading to cyclization of 2, 3 oxidosqualene, which is a key metabolite to further diversify to a myriad of phytochemicals. In contrast to the available reports on the studies of WsCAS in withanolide biosynthesis, its involvement in phytosterol biosynthesis needs investigation. Present work deals with the understanding of role of WsCAS triterpenoid synthase gene in the regulation of biosynthesis of phytosterols & withanolides. Docking studies of WsCAS protein revealed Conserved amino acids, DCATE motif, and QW motif which are involved in efficient substrate binding, structure stabilization, and catalytic activity. Overexpression/silencing of WsCAS leading to increment/decline of phytosterols confers its stringent regulation in phytosterols biosynthesis. Differential regulation of WsCAS on the metabolic flux towards phytosterols and withanolide biosynthesis was observed under abiotic stress conditions. The preferential channelization of 2, 3 oxidosqualene towards withanolides and/or phytosterols occurred under heat/salt stress and cold/water stress, respectively. Stigmasterol and ß-sitosterol showed major contribution in high/low temperature and salt stress, and campesterol in water stress management. Overexpression of WsCAS in Arabidopsis thaliana led to the increment in phytosterols in general. Thus, the WsCAS plays important regulatory role in the biosynthetic pathway of phytosterols and withanolides under abiotic stress conditions.

Multimodal Hox5 activity generates motor neuron diversity.

Motor neurons (MNs) are the final output of circuits driving fundamental behaviors, such as respiration and locomotion. Hox proteins are essential in generating the MN diversity required for accomplishing these functions, but the transcriptional mechanisms that enable Hox paralogs to assign distinct MN subtype identities despite their promiscuous DNA binding motif are not well understood. Here we show that Hoxa5 controls chromatin accessibility in all mouse spinal cervical MN subtypes and engages TALE co-factors to directly bind and regulate subtype-specific genes. We identify a paralog-specific interaction of Hoxa5 with the phrenic MN-specific transcription factor Scip and show that heterologous expression of Hoxa5 and Scip is sufficient to suppress limb-innervating MN identity. We also demonstrate that phrenic MN identity is stable after Hoxa5 downregulation and identify Klf proteins as potential regulators of phrenic MN maintenance. Our data identify multiple modes of Hoxa5 action that converge to induce and maintain MN identity.

Cutaneous Arsenical Exposure Induces Distinct Metabolic Transcriptional Alterations of Kidney Cells.

Arsenicals are deadly chemical warfare agents that primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenical exposure is also known to cause acute kidney injury, a condition that contributes to arsenical-associated death due to the necessity of the kidney in maintaining whole-body fluid homeostasis. Because of the global health risk that arsenicals pose, a nuanced understanding of how arsenical exposure can lead to kidney injury is needed. We used a nontargeted transcriptional approach to evaluate the effects of cutaneous exposure to phenylarsine oxide, a common arsenical, in a murine model. Here we identified an upregulation of metabolic pathways such as fatty acid oxidation, fatty acid biosynthesis, and peroxisome proliferator-activated receptor (PPAR)-α signaling in proximal tubule epithelial cell and endothelial cell clusters. We also revealed highly upregulated genes such as Zbtb16, Cyp4a14, and Pdk4, which are involved in metabolism and metabolic switching and may serve as future therapeutic targets. The ability of arsenicals to inhibit enzymes such as pyruvate dehydrogenase has been previously described in vitro. This, along with our own data, led us to conclude that arsenical-induced acute kidney injury may be due to a metabolic impairment in proximal tubule and endothelial cells and that ameliorating these metabolic effects may lead to the development of life-saving therapies. SIGNIFICANCE STATEMENT: In this study, we demonstrate that cutaneous arsenical exposure leads to a transcriptional shift enhancing fatty acid metabolism in kidney cells, indicating that metabolic alterations might mechanistically link topical arsenical exposure to acute kidney injury. Targeting metabolic pathways may generate promising novel therapeutic approaches in combating arsenical-induced acute kidney injury.

Arsenic exposure to mouse visceral leishmaniasis model through their drinking water linked to the disease exacerbation via modulation in host protective immunity: a preclinical study.

A large body of evidence has shown a direct link between arsenic exposure and drug resistance to Leishmania parasites against antimonial preparations in visceral leishmaniasis (VL) hyper-endemic regions, especially in India and its sub-continent. However, the implicated roles of arsenic on the VL host, pathophysiological changes, and immune function have not yet been clarified, particularly at the reported concentration of arsenic in the VL hyper-endemic area of Bihar, India. Herein, we exposed the mouse VL model to arsenic (0.5 mg/L to 2 mg/L) through their drinking water and analyzed its effect on T cells proliferation, Th1/Th2-mediators, MAPK signaling cascade, and parasite load in preclinical models. Coherently, the parasite count in Giemsa stained spleen imprint has been investigated and found significant positive associations with levels of arsenic exposure. The liver and kidney function tests (AST, ALT, ALP, BUN, Creatinine, Urea, etc.) are apparent to hepatonephric toxicity in arsenic exposed VL mice compared to unexposed. This observation appears to be consistent with the up-regulated expression of immune regulatory Th2 mediators (IL-4, IL-10, TGF-ß) and down-regulated expression of Th1 mediators (IL-12, IFN-γ, TNF-α) with a suppressed leishmanicidal function of macrophage (ROS, NO, iNOS). We also established that arsenic exposure modulated the host ERK-1/2 and p38 MAPK signaling cascade, limited T lymphocyte proliferation, and a lower IgG2a/IgG1 ratio to favor the Leishmania parasite survival inside the host. This study suggests that the contorted Th1-subtype and exacerbated Th2-subtype immune responses are involved in the increased susceptibility and pathogenesis of Leishmania parasite among subjects/individuals regularly exposed to arsenic.

Microneedle-mediated transdermal delivery of N-acetyl cysteine as a potential antidote for lewisite injury.

Lewisite is a chemical warfare agent intended for use in World War and a potential threat to the civilian population due to presence in stockpiles or accidental exposure. Lewisite-mediated skin injury is characterized by acute erythema, pain, and blister formation. N-acetyl cysteine (NAC) is an FDA-approved drug for acetaminophen toxicity, identified as a potential antidote against lewisite. In the present study, we have explored the feasibility of rapid NAC delivery through transdermal route for potentially treating chemical warfare toxicity. NAC is a small, hydrophilic molecule with limited passive delivery through the skin. Using skin microporation with dissolving microneedles significantly enhanced the delivery of NAC into and across dermatomed human skin in our studies. Microporation followed by application of solution (poke-and-solution) resulted in the highest in vitro delivery (509.84 ± 155.04 µg/sq·cm) as compared to poke-and-gel approach (474.91 ± 70.09 µg/sq·cm) and drug-loaded microneedles (226.89 ± 33.41 µg/sq·cm). The lag time for NAC delivery through poke-and-solution approach (0.23 ± 0.04 h) was close to gel application (0.25 ± 0.02 h), with the highest for drug-loaded microneedles (1.27 ± 1.16 h). Thus, we successfully demonstrated the feasibility of rapid NAC delivery using various skin microporation approaches for potential treatment against lewisite-mediated skin toxicity.

Novel low-temperature synthesis of Y2-x O3 :Eux 3+ nanophosphor using combustion with thioglycerol as fuel for near-UV light-emitting diodes.

Luminescent materials used in flat panel displays, compact fluorescent lamps, and light-emitting diodes require high purity, uniform particle size, clean surfaces, spherical shape, and dense morphology to ensure long-term stability. Y2 O3 :Eu3+ is a widely studied red phosphor known for its characteristic photoluminescence (PL) emission at 613 nm with near-UV excitation at 392 nm. Many methods have been explored to synthesize Y2 O3 :Eu3+ nanoparticles with exceptional purity, consistent phases, and uniform particle sizes. The aim is to synthesize particles with pristine surfaces, spherical shape, and compact morphology. This study focuses on the low-temperature synthesis and PL investigation of Y2-x O3 :Eux 3+ nanophosphors using combustion with thioglycerol as fuel. The results are compared with Y2-x O3 :Eux 3+ red nanophosphors synthesized using wet chemical and nitrate combustion methods. The PL characteristics of the Y2-x O3 :Eux 3+ nanophosphors were analyzed using PL emission spectroscopy, X-ray diffraction, and scanning electron microscopy. These findings highlight the advantageous properties of the synthesized nanophosphors, such as their suitability for solid-state lighting applications in the lamp industry as highly efficient red phosphors. The combination of high purity, uniform particle size, clean surfaces, spherical shape, and dense morphology contributes to their potential for long-term stability and reliable performance in lighting devices.

Comparative Study of the Effect of Liraglutide and Donepezil on Learning and Memory in Diazepam-Induced Amnesic Albino Rats.

Background Dementia is an age-related gradual loss of memory that is progressive in nature. Presently, the most common cause of dementia is Alzheimer's disease (AD), which is treated with donepezil, an anticholinesterase. But it only provides short-term symptomatic improvement. Liraglutide, which is an anti-diabetic drug, stimulates the anti-apoptotic pathway of nerve damage, which helps in regenerating nerve cells; so, it may help in dementia cases. Therefore, this study aimed to explore the effect of liraglutide on learning and memory and to compare its effect with donepezil in diazepam-induced amnesic albino rats. Methodology Twenty healthy male Albino rats weighing 150-200 grams were taken and divided into four groups: A, B, C, and D. Group A rats were normal rats, whereas the rats in groups B, C, and D were made amnesic by the intraperitoneal (i.p.) administration of 0.1 mg per kg of diazepam. Immediately after producing amnesia, group B rats received normal saline, group C received liraglutide, and group D received donepezil through the intraperitoneal route as test drugs. Group A rats received only normal saline. The amnesic effect was measured by the escape latency period, which was measured by using a Morris Water Maize (MWM) instrument. Escape latency is the time (in seconds) to locate the platform from the starting point. The amnesic effect is shown by an increase in escape latency and the anti-amnesic effect by a decrease in escape latency. Escape latency was recorded at 0 hr, 1 hr, 2 hr, 3 hr, and 4 hr after test drug administration. Results Group B rats showed an increase in escape latency, which shows the amnesic effect of diazepam. When group C and group D amnesic rats were treated with liraglutide and donepezil, respectively, a one-hour after-treatment increase in escape latency was seen but after two hours, both groups showed a decrease in escape latency, which indicates the anti-amnesic effect of both drugs. When groups C and D were compared, and the post-hoc highly significant difference (HSD) test was used, there was no significant difference between the two drugs, although the liraglutide-treated group (C) showed a lower anti-amnesic effect. However, group C showed a significant effect as compared to group B rats (p-value <0.05), which indicates the anti-amnesic property of liraglutide as compared to normal saline. Conclusion Liraglutide shows an anti-amnesic property. Since it works by a mechanism different from donepezil, it can be used as add-on therapy with donepezil in dementia patients.

PCR inhibitors and facilitators - Their role in forensic DNA analysis.

Since its inception, DNA typing technology has been practiced as a robust tool in criminal investigations. Experts usually utilize STR profiles to identify and individualize the suspect. However, mtDNA and Y STR analyses are also considered in some sample-limiting conditions. Based on DNA profiles thus generated, forensic scientists often opine the results as Inclusion, exclusion, and inconclusive. Inclusion and exclusion were defined as concordant results; the inconclusive opinions create problems in conferring justice in a trial- since nothing concrete can be interpreted from the profile generated. The presence of inhibitor molecules in the sample is the primary factor behind these indefinite results. Recently, researchers have been emphasizing studying the sources of PCR inhibitors and their mechanism of inhibition. Furthermore, several mitigation strategies- to facilitate the DNA amplification reaction -have now found their place in the routine DNA typing assays with compromised biological samples. The present review paper attempts to provide a comprehensive review of PCR inhibitors, their source, mechanism of inhibition, and ways to mitigate their effect using PCR facilitators.

Cellular senescence in hepatocytes contributes to metabolic disturbances in NASH.

Cellular senescence is a state of irreversible cell cycle arrest and has been shown to play a key role in many diseases, including metabolic diseases. To investigate the potential contribution of hepatocyte cellular senescence to the metabolic derangements associated with non-alcoholic steatohepatitis (NASH), we treated human hepatocyte cell lines HepG2 and IHH with the senescence-inducing drugs nutlin-3a, doxorubicin and etoposide. The senescence-associated markers p16, p21, p53 and beta galactosidase were induced upon drug treatment, and this was associated with increased lipid storage, increased expression of lipid transporters and the development of hepatic steatosis. Drug-induced senescence also led to increased glycogen content, and increased VLDL secretion from hepatocytes. Senescence was also associated with an increase in glucose and fatty acid oxidation capacity, while de novo lipogenesis was decreased. Surprisingly, cellular senescence caused an overall increase in insulin signaling in hepatocytes, with increased insulin-stimulated phosphorylation of IR, Akt, and MAPK. Together, these data indicate that hepatic senescence plays a causal role in the development of NASH pathogenesis, by modulating glucose and lipid metabolism, favoring steatosis. Our findings contribute to a better understanding of the mechanisms linking cellular senescence and fatty liver disease and support the development of new therapies targeting senescent cells for the treatment of NASH.

BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH.

The role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets.

Chronic hyperinsulinemia promotes human hepatocyte senescence.

OBJECTIVE: Cellular senescence, an irreversible proliferative cell arrest, is caused by excessive intracellular or extracellular stress/damage. Increased senescent cells have been identified in multiple tissues in different metabolic and other aging-related diseases. Recently, several human and mouse studies emphasized the involvement of senescence in development and progression of NAFLD. Hyperinsulinemia, seen in obesity, metabolic syndrome, and other conditions of insulin resistance, has been linked to senescence in adipocytes and neurons. Here, we investigate the possible direct role of chronic hyperinsulinemia in the development of senescence in human hepatocytes. METHODS: Using fluorescence microscopy, immunoblotting, and gene expression, we tested senescence markers in human hepatocytes subjected to chronic hyperinsulinemia in vitro and validated the data in vivo by using liver-specific insulin receptor knockout (LIRKO) mice. The consequences of hyperinsulinemia were also studied in senescent hepatocytes following doxorubicin as a model of stress-induced senescence. Furthermore, the effects of senolytic agents in insulin- and doxorubicin-treated cells were analyzed. RESULTS: Results showed that exposing the hepatocytes to prolonged hyperinsulinemia promotes the onset of senescence by increasing the expression of p53 and p21. It also further enhanced the senescent phenotype in already senescent hepatocytes. Addition of insulin signaling pathway inhibitors prevented the increase in cell senescence, supporting the direct contribution of insulin. Furthermore, LIRKO mice, in which insulin signaling in the liver is abolished due to deletion of the insulin receptor gene, showed no differences in senescence compared to their wild-type counterparts despite having marked hyperinsulinemia indicating these are receptor-mediated effects. In contrast, the persistent hyperinsulinemia in LIRKO mice enhanced senescence in white adipose tissue. In vitro, senolytic agents dasatinib and quercetin reduced the prosenescent effects of hyperinsulinemia in hepatocytes. CONCLUSION: Our findings demonstrate a direct link between chronic hyperinsulinemia and hepatocyte senescence. This effect can be blocked by reducing the levels of insulin receptors or administration of senolytic drugs, such as dasatinib and quercetin.

Role of hair follicles in the pathogenesis of arsenical-induced cutaneous damage.

Arsenical vesicants cause skin inflammation, blistering, and pain. The lack of appropriate animal models causes difficulty in defining their molecular pathogenesis. Here, Ptch1+/- /C57BL/6 mice were employed to investigate the pathobiology of the arsenicals lewisite and phenylarsine oxide (PAO). Following lewisite or PAO challenge (24 h), the skin of animals becomes grayish-white, thick, leathery, and wrinkled with increased bi-fold thickness, Draize score, and necrotic patches. In histopathology, infiltrating leukocytes (macrophages and neutrophils), epidermal-dermal separation, edema, apoptotic cells, and disruption of tight and adherens junction proteins can be visualized. PCR arrays and nanoString analyses showed significant increases in cytokines/chemokines and other proinflammatory mediators. As hair follicles (HFs), which provide an immune-privileged environment, may affect immune cell trafficking and consequent inflammatory responses, we compared the pathogenesis of these chemicals in this model to that in Ptch1+/- /SKH-1 hairless mice. Ptch1+/- /SKH-1 mice have rudimentary, whereas Ptch1+/- /C57BL/6 mice have well-developed HFs. Although no significant differences were observed in qualitative inflammatory responses between the two strains, levels of cytokines/chemokines differed. Importantly, the mechanism of inflammation was identical; both reactive oxygen species induction and consequent activation of unfolded protein response signaling were similar. These data reveal that the acute molecular pathogenesis of arsenicals in these two murine models is similar.

ETS1 is a novel transcriptional regulator of adult T-cell leukemia/lymphoma of North American descent.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell lymphoma associated with the human T-cell lymphotropic virus type 1 virus endemic in regions including Japan, the Caribbean islands, and Latin America. Although progress has been made to understand the disease, survival outcomes with current standard therapy remain extremely poor particularly in acute ATLL, underlying the need for better understanding of its biology and identification of novel therapeutic targets. Recently, it was demonstrated that ATLL of North American-descendent patients (NA-ATLL) is both clinically and molecularly distinct from Japanese-descendent (J-ATLL), with inferior prognosis and higher incidence of epigenetic-targeting mutations compared with J-ATLL. In this study, combined chromatin accessibility and transcriptomic profiling were used to further understand the key transcriptional regulators of NA-ATLL compared with J-ATLL. The ETS1 motif was found to be enriched in chromatin regions that were differentially open in NA-ATLL, whereas the AP1/IRF4 motifs were enriched in chromatin regions more open in J-ATLL. ETS1 expression was markedly elevated in NA-ATLL in both cell line and primary tumor samples, and knockdown of ETS1 in NA-ATLL cells resulted in inhibition of cell growth. CCR4, a previously identified oncogenic factor in ATLL, was found to be a direct ETS1 transcriptional target in NA-ATLL. As such, ETS1 provides an alternate mechanism to enhance CCR4 expression/activity in NA-ATLL, even in the absence of activating CCR4 mutations (CCR4 mutations were identified in 4 of 9 NA-ATLL cases). Taken together, this study identifies ETS1 as a novel dominant oncogenic transcriptional regulator in NA-ATLL.